Poly(phosphoesters) for delivery of nucleic acids

ABSTRACT

Disclosed are polymers comprising the moiety A, which is a moiety of formula I: and pharmaceutically acceptable salts thereof, wherein R, R 1 , R 2 , L, n1 and n2 are as defined herein. These polymers are useful for delivering nucleic acids to subject. These polymers and pharmaceutically acceptable compositions comprising such polymers and nucleic acids can be useful for treating various diseases, disorders and conditions.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims benefit of U.S. Provisional ApplicationNo. 62/518,313, filed Jun. 12, 2017, which is hereby incorporated byreference in its entirety.

SEQUENCE LISTING

The present specification makes reference to a Sequence Listing providedin electronic form as an ASCII.txt file named “MRT-1248WO_ST25.txt” thatwas generated on Jun. 11, 2018, and is 3,013 bytes in size.

BACKGROUND

Nucleic acids have been explored as a potential therapeutic option forcertain disease states. In particular, ribonucleic acid (RNA)interference (RNAi) using, for example, small interfering RNA (siRNA),short hairpin RNA (shRNA), and antisense RNA (aRNA) approaches have beenthe subject of significant research and clinical development, forexample, for binding to messenger RNA (mRNA), long non-coding RNA(IncRNA), micro-RNA (miRNA) and other endogenous targets. More recently,administration of mRNA, multimeric coding nucleic acid (MCNA), polymericcoding nucleic acid (PCNA), guide RNA (gRNA) and CRISPR RNA (crRNA) havebeen investigated as possible treatments of various diseases. However,the delivery of nucleic acids as therapeutics remains a challenge.

SUMMARY

The present invention provides, among other things, polymers useful indelivering nucleic acids as a therapeutic. The invention is based, inpart, on the surprising discovery that the polymers described hereinprovide safe and efficient delivery of nucleic acids, such as mRNA. Inparticular, the polymers of the present invention may provide one ormore advantages over other polymers. For example, as described in moredetail herein, the polymers of the present invention may provideenhanced endosomal release of the nucleic acid being delivered by thepolymer. Additionally, the biodegradable nature of the polymer mayprovide greater patient tolerability than other polymeric deliveryvehicles. Thus, the polymers of the present invention may provide morepotent and/or safer nucleic acid delivery for the treatment of a varietyof diseases.

In some aspects, the present invention provides a polymer comprising themoiety A: A, which is a moiety of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   each instance of R¹ independently is —H or a C₁-C₂₀ aliphatic        group;    -   each instance of R² independently is —H or a C₁-C₂₀ aliphatic        group;    -   each instance of R³ independently is —H or a C₁-C₂₀ aliphatic        group;    -   X is independently S or O;    -   n1 is an integer from 1 to 6;    -   n2 is an integer from 1 to 6;    -   R is N or CH; and    -   L is C₁₋₆ alkyl or a protonatable group provided that when R is        CH then L is a protonatable group, wherein the protonatable        group comprises at least one 1° amino, 2° amino, 3° amino or        imidazolyl group.

In some aspects, the present invention provides methods of preparing thepolymers of the present invention.

In some aspects, the present invention provides a pharmaceuticalcomposition (a “provided composition”) comprising a polymer of thepresent invention and one or more nucleic acids or polynucleotides.

In some aspects, the present invention provides methods of treating adisease in a subject comprising administering to the subject a providedcomposition.

Definitions

In order for the present invention to be more readily understood,certain terms are first defined below. Additional definitions for thefollowing terms and other terms are set forth throughout thespecification. The publications and other reference materials referencedherein to describe the background of the invention and to provideadditional detail regarding its practice are hereby incorporated byreference for all purposes.

As used in this Specification and the appended claims, the singularforms “a,” “an” and “the” include plural referents unless the contextclearly dictates otherwise.

Unless specifically stated or obvious from context, as used herein, theterm “or” is understood to be inclusive and covers both “or” and “and”.

The terms “e.g.,” and “i.e.” as used herein, are used merely by way ofexample, without limitation intended, and should not be construed asreferring only those items explicitly enumerated in the specification.

The terms “or more”, “at least”, “more than”, and the like, e.g., “atleast one” are understood to include but not be limited to at least 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39,40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57,58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75,76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93,94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108,109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122,123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136,137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149 or 150,200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000 ormore than the stated value. Also included is any greater number orfraction in between.

The terms “plurality”, “at least two”, “two or more”, “at least second”,and the like, are understood to include but not limited to at least 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58,59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76,77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94,95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109,110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123,124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137,138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149 or 150, 200,300, 400, 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000 or more.Also included is any greater number or fraction in between.

Throughout the specification the word “comprising,” or variations suchas “comprises” or “comprising,” will be understood to imply theinclusion of a stated element, integer or step, or group of elements,integers or steps, but not the exclusion of any other element, integeror step, or group of elements, integers or steps.

Approximately or about: As used herein, the term “approximately” or“about,” as applied to one or more values of interest, refers to a valuethat is similar to a stated reference value. In certain embodiments, theterm “approximately” or “about” refers to a range of values that fallwithin 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%,8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greaterthan or less than) of the stated reference value unless otherwise statedor otherwise evident from the context (except where such number wouldexceed 100% of a possible value).

Amino acid: As used herein, the term “amino acid,” in its broadestsense, refers to any compound and/or substance that can be incorporatedinto a polypeptide chain. In some embodiments, an amino acid has thegeneral structure H₂N—C(H)(R)—COOH. In some embodiments, an amino acidis a naturally occurring amino acid. In some embodiments, an amino acidis a modified amino acid; in some embodiments, an amino acid is ad-amino acid; in some embodiments, an amino acid is an I-amino acid.“Standard amino acid” refers to any of the twenty standard I-amino acidscommonly found in naturally occurring peptides. “Nonstandard amino acid”refers to any amino acid, other than the standard amino acids,regardless of whether it is prepared synthetically or obtained from anatural source. As used herein, “modified amino acid” encompasses achemically modified amino acids, including but not limited to salts,amino acid derivatives (such as amides), and/or substitutions. Aminoacids, including carboxy- and/or amino-terminal amino acids in peptides,can be modified by methylation, amidation, acetylation, protectinggroups, and/or substitution with other chemical groups that can changethe peptide's circulating half-life without adversely affecting theiractivity. Amino acids may participate in a disulfide bond. Amino acidsmay comprise one or posttranslational modifications, such as associationwith one or more chemical entities (e.g., methyl groups, acetate groups,acetyl groups, phosphate groups, formyl moieties, isoprenoid groups,sulfate groups, polyethylene glycol moieties, lipid moieties,carbohydrate moieties, biotin moieties, etc.). The term “amino acid” isused interchangeably with “amino acid residue,” and may refer to a freeamino acid and/or to an amino acid residue of a peptide. It will beapparent from the context in which the term is used whether it refers toa free amino acid or a residue of a peptide.

Animal: As used herein, the term “animal” refers to any member of theanimal kingdom. In some embodiments, “animal” refers to humans, at anystage of development. In some embodiments, “animal” refers to non-humananimals, at any stage of development. In certain embodiments, thenon-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit,a monkey, a dog, a cat, a sheep, cattle, a primate, and/or a pig). Insome embodiments, animals include, but are not limited to, mammals,birds, reptiles, amphibians, fish, insects, and/or worms. In someembodiments, an animal may be a transgenic animal,genetically-engineered animal, and/or a clone.

Biologically active: As used herein, the term “biologically active”refers to a characteristic of any agent that has activity in abiological system, and particularly in an organism. For instance, anagent that, when administered to an organism, has a biological effect onthat organism, is considered to be biologically active.

Delivery: As used herein, the term “delivery” refers to delivery of acomposition to an organism, including but not limited to an animal orhuman. For delivery to a multi-tissue organism, delivery encompassesboth local and systemic delivery. For example, delivery of a nucleicacid such as mRNA encompasses situations in which an mRNA is deliveredto a target tissue and the encoded protein is expressed and retainedwithin the target tissue (also referred to as “local distribution” or“local delivery”), and situations in which an mRNA is delivered to atarget tissue and the encoded protein is expressed and secreted intopatient's circulation system (e.g., serum) and systematicallydistributed and taken up by other tissues (also referred to as “systemicdistribution” or “systemic delivery).

Expression: As used herein, “expression” of a nucleic acid sequencerefers to one or more of the following events: (1) production of an mRNAtemplate from a DNA sequence (e.g., by transcription); (2) processing ofan mRNA transcript (e.g., by splicing, editing, 5′ cap formation, and/or3′ end formation); (3) translation of an mRNA into a polypeptide orprotein; and/or (4) post-translational modification of a polypeptide orprotein. In this application, the terms “expression” and “production,”and grammatical equivalent, are used inter-changeably.

Functional: As used herein, a “functional” biological molecule is abiological molecule in a form in which it exhibits a property and/oractivity by which it is characterized.

Half-life: As used herein, the term “half-life” is the time required fora quantity such as nucleic acid or protein concentration or activity tofall to half of its value as measured at the beginning of a time period.

Improve, increase, or reduce: As used herein, the terms “improve,”“increase” or “reduce,” or grammatical equivalents, indicate values thatare relative to a baseline measurement, such as a measurement in thesame individual prior to initiation of the treatment described herein,or a measurement in a control sample or subject (or multiple controlsamples or subjects) in the absence of the treatment described herein. A“control subject” is a subject afflicted with the same form of diseaseas the subject being treated, who is about the same age as the subjectbeing treated.

In Vitro: As used herein, the term “in vitro” refers to events thatoccur in an artificial environment, e.g., in a test tube or reactionvessel, in cell culture, etc., rather than within a multi-cellularorganism.

In Vivo: As used herein, the term “in vivo” refers to events that occurwithin a multi-cellular organism, such as a human and a non-humananimal. In the context of cell-based systems, the term may be used torefer to events that occur within a living cell (as opposed to, forexample, in vitro systems).

Isolated: As used herein, the term “isolated” refers to a substanceand/or entity that has been (1) separated from at least some of thecomponents with which it was associated when initially produced (whetherin nature and/or in an experimental setting), and/or (2) produced,prepared, and/or manufactured by the hand of man. Isolated substancesand/or entities may be separated from about 10%, about 20%, about 30%,about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%,about 98%, about 99%, or more than about 99% of the other componentswith which they were initially associated. In some embodiments, isolatedagents are about 80%, about 85%, about 90%, about 91%, about 92%, about93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%,or more than about 99% pure. As used herein, a substance is “pure” if itis substantially free of other components. As used herein, calculationof percent purity of isolated substances and/or entities should notinclude excipients (e.g., buffer, solvent, water, etc.).

messenger RNA (mRNA): As used herein, the term “messenger RNA (mRNA)” or“mRNA” refers to a polynucleotide that encodes at least one polypeptide.mRNA as used herein encompasses both modified and unmodified RNA. mRNAmay contain one or more coding and non-coding regions. mRNA can bepurified from natural sources, produced using recombinant expressionsystems or plasmid-based expression systems or in vitro transcription(IVT) systems, and optionally purified and/or modified, or produced bychemical synthesis. In some embodiments, for example, for mRNA producedusing recombinant or plasmid-based expression systems or produced bychemical synthesis, the mRNA coding region, the mRNA non-coding region,or both the mRNA coding and non-coding regions, can include a uniquenucleic acid sequence (having modified or unmodified nucleic acids),i.e., that is different from natural and/or known nucleic acid sequencesfor that mRNA. For example, in some embodiments, the mRNA coding regioncan include one or more codons that have a different triplet nucleicacid sequence than the triplet nucleic acid sequence of thecorresponding codons in the corresponding natural or known mRNA(referred to herein as a “codon-optimized” sequence). An mRNA sequenceis presented in the 5′ to 3′ direction unless otherwise indicated. Insome embodiments, “mRNA” can encompass both unmodified RNA and modifiedmRNA (mmRNA). The modifications in mmRNA can comprise nucleoside analogssuch as analogs having one or more chemically modified bases or sugars,backbone modifications, or other modifications described herein. In someembodiments, an mRNA is or comprises natural nucleosides (e.g.,adenosine, guanosine, cytidine, uridine); nucleoside analogs (e.g.,2-aminoadenosine, 2-thiothymidine, inosine, pyrrolo-pyrimidine, 3-methyladenosine, 5-methylcytidine, C-5 propynyl-cytidine, C-5propynyl-uridine, 2-aminoadenosine, C5-bromouridine, C5-fluorouridine,C5-iodouridine, C5-propynyl-uridine, C5-propynyl-cytidine,C5-methylcytidine, 2-aminoadenosine, 7-deazaadenosine, 7-deazaguanosine,8-oxoadenosine, 8-oxoguanosine, O(6)-methylguanine, and 2-thiocytidine);chemically modified bases; biologically modified bases (e.g., methylatedbases); intercalated bases; modified sugars (e.g., 2′-fluororibose,ribose, 2′-deoxyribose, arabinose, and hexose); and/or modifiedphosphate groups (e.g., phosphorothioates and 5′-N-phosphoramiditelinkages).

Nucleic acid: As used herein, the term “nucleic acid,” in its broadestsense, refers to any compound and/or substance that is or can beincorporated into a polynucleotide chain. In some embodiments, a nucleicacid is a compound and/or substance that is or can be incorporated intoa polynucleotide chain via a phosphodiester linkage. In someembodiments, “nucleic acid” refers to individual nucleic acid residues(e.g., nucleotides and/or nucleosides). In some embodiments, “nucleicacid” refers to a polynucleotide chain comprising individual nucleicacid residues. In some embodiments, “nucleic acid” encompassesribonucleic acids (RNA), including but not limited to any one or more ofinterference RNAs (RNAi), small interfering RNA (siRNA), short hairpinRNA (shRNA), antisense RNA (aRNA), messenger RNA (mRNA), modifiedmessenger RNA (mmRNA), long non-coding RNA (IncRNA), micro-RNA (miRNA)multimeric coding nucleic acid (MCNA), polymeric coding nucleic acid(PCNA), guide RNA (gRNA) and CRISPR RNA (crRNA). In some embodiments,“nucleic acid” encompasses deoxyribonucleic acid (DNA), including butnot limited to any one or more of single-stranded DNA (ssDNA),double-stranded DNA (dsDNA) and complementary DNA (cDNA). In someembodiments, “nucleic acid” encompasses both RNA and DNA. Inembodiments, DNA may be in the form of antisense DNA, plasmid DNA, partsof a plasmid DNA, pre-condensed DNA, a product of a polymerase chainreaction (PCR), vectors (e.g., P1, PAC, BAC, YAC, artificialchromosomes), expression cassettes, chimeric sequences, chromosomal DNA,or derivatives of these groups. In embodiments, RNA may be in the formof messenger RNA (mRNA), ribosomal RNA (rRNA), signal recognitionparticle RNA (7 SL RNA or SRP RNA), transfer RNA (tRNA),transfer-messenger RNA (tmRNA), small nuclear RNA (snRNA), smallnucleolar RNA (snoRNA), SmY RNA, small Cajal body-specific RNA (scaRNA),guide RNA (gRNA), ribonuclease P (RNase P), Y RNA, telomerase RNAcomponent (TERC), spliced leader RNA (SL RNA), antisense RNA (aRNA orasRNA), cis-natural antisense transcript (cis-NAT), CRISPR RNA (crRNA),long noncoding RNA (IncRNA), micro-RNA (miRNA), piwi-interacting RNA(piRNA), small interfering RNA (siRNA), transacting siRNA (tasiRNA),repeat associated siRNA (rasiRNA), 73K RNA, retrotransposons, a viralgenome, a viroid, satellite RNA, or derivatives of these groups. In someembodiments, a nucleic acid is a mRNA encoding a protein such as anenzyme.

Patient: As used herein, the term “patient” or “subject” refers to anyorganism to which a provided composition may be administered, e.g., forexperimental, diagnostic, prophylactic, cosmetic, and/or therapeuticpurposes. Typical patients include animals (e.g., mammals such as mice,rats, rabbits, non-human primates, and/or humans). In some embodiments,a patient is a human. A human includes pre- and post-natal forms.

Pharmaceutically acceptable: The term “pharmaceutically acceptable”, asused herein, refers to substances that, within the scope of soundmedical judgment, are suitable for use in contact with the tissues ofhuman beings and animals without excessive toxicity, irritation,allergic response, or other problem or complication, commensurate with areasonable benefit/risk ratio.

Pharmaceutically acceptable salt: Pharmaceutically acceptable salts arewell known in the art. For example, S. M. Berge et al., describespharmaceutically acceptable salts in detail in J. PharmaceuticalSciences (1977) 66:1-19. Pharmaceutically acceptable salts of thecompounds of this invention include those derived from suitableinorganic and organic acids and bases. Examples of pharmaceuticallyacceptable, nontoxic acid addition salts are salts of an amino groupformed with inorganic acids such as hydrochloric acid, hydrobromic acid,phosphoric acid, sulfuric acid and perchloric acid or with organic acidssuch as acetic acid, oxalic acid, maleic acid, tartaric acid, citricacid, succinic acid or rnalonic acid or by using other methods used inthe art such as ion exchange. Other pharmaceutically acceptable saltsinclude adipate, alginate, ascorbate, aspartate, benzenesulfonate,benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate,citrate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate,gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄ alkyl)₄ salts. Representativealkali or alkaline earth metal salts include sodium, lithium, potassium,calcium, magnesium, and the like. Further pharmaceutically acceptablesalts include, when appropriate, nontoxic ammonium. quaternary ammonium,and amine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, sulfonate and aryl sulfonate.Further pharmaceutically acceptable salts include salts formed from thequarternization of an amine using an appropriate electrophile, e.g., analkyl halide, to form a quarternized alkylated amino salt.

Systemic distribution or delivery: As used herein, the terms “systemicdistribution,” “systemic delivery,” or grammatical equivalent, refer toa delivery or distribution mechanism or approach that affect disparatecompartments or tissues of the entire body or of an entire organism.Typically, systemic distribution or delivery is accomplished via body'scirculation system, e.g., blood stream. Compared to the definition of“local distribution or delivery.”

Subject: As used herein, the term “subject” refers to a human or anynon-human animal (e.g., mouse, rat, rabbit, dog, cat, cattle, swine,sheep, horse or primate). A human includes pre- and post-natal forms. Inmany embodiments, a subject is a human being. A subject can be apatient, which refers to a human presenting to a medical provider fordiagnosis or treatment of a disease. The term “subject” is used hereininterchangeably with “individual” or “patient.” A subject can beafflicted with or is susceptible to a disease or disorder but may or maynot display symptoms of the disease or disorder.

Substantially: As used herein, the term “substantially” refers to thequalitative condition of exhibiting total or near-total extent or degreeof a characteristic or property of interest. One of ordinary skill inthe biological arts will understand that biological and chemicalphenomena rarely, if ever, go to completion and/or proceed tocompleteness or achieve or avoid an absolute result. The term“substantially” is therefore used herein to capture the potential lackof completeness inherent in many biological and chemical phenomena.

Target tissues: As used herein, the term “target tissues” refers to anytissue that is affected by a disease to be treated. In some embodiments,target tissues include those tissues that display disease-associatedpathology, symptom, or feature.

Therapeutically effective amount: As used herein, the term“therapeutically effective amount” of a therapeutic agent means anamount that is sufficient, when administered to a subject suffering fromor susceptible to a disease, disorder, and/or condition, to treat,diagnose, prevent, and/or delay the onset of the symptom(s) of thedisease, disorder, and/or condition. It will be appreciated by those ofordinary skill in the art that a therapeutically effective amount istypically administered via a dosing regimen comprising at least one unitdose.

Treating: As used herein, the term “treat,” “treatment,” or “treating”refers to any method used to partially or completely alleviate,ameliorate, relieve, inhibit, prevent, delay onset of, reduce severityof and/or reduce incidence of one or more symptoms or features of aparticular disease, disorder, and/or condition. Treatment may beadministered to a subject who does not exhibit signs of a disease and/orexhibits only early signs of the disease for the purpose of decreasingthe risk of developing pathology associated with the disease.

Aliphatic: As used herein, the term aliphatic refers to both C₁-C₄₀hydrocarbons and includes both saturated and unsaturated hydrocarbons.An aliphatic may be linear, branched, or cyclic. For example, C₁-C₂₀aliphatics can include C₁-C₂₀ saturated alkyls (e.g., linear or branchedC₁-C₂₀ saturated alkyls), C₂-C₂₀ alkenyls (e.g., linear or branchedC₄-C₂₀ dienyls, linear or branched C₆-C₂₀ trienyls, and the like), andC₂-C₂₀ alkynyls (e.g., linear or branched C₂-C₂₀ alkynyls). C₁-C₂₀aliphatics can include C₃-C₂₀ cyclic aliphatics (e.g., C₃-C₂₀cycloalkyls, C₄-C₂₀ cycloalkenyls, or C₈-C₂₀ cycloalkynyls). The term“alkylene,” as used herein, represents a saturated divalent straight orbranched chain hydrocarbon group and is exemplified by methylene,ethylene, isopropylene and the like. In certain embodiments, thealiphatic may comprise one or more cyclic aliphatic and/or one or moreheteroatoms such as oxygen, nitrogen, or sulfur and may optionally besubstituted with one or more substituents such as alkyl, halo, alkoxyl,hydroxy, amino, aryl, ether, ester or amide. For example, an aliphaticmay be substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6independently selected substituents) of halogen, —CO₂R′, —CN, —OH, —OR′,—NH₂, —NHR′, —N(R^(J1))₂, —SR′ or —SO₂R′, wherein each instance of R′independently is C₁₋₃ alkyl. In certain embodiments, the aliphatic isunsubstituted. In certain embodiments, the aliphatic does not includeany heteroatoms.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS Polymers—Moiety A

In some aspects, the present invention provides a polymer comprising themoiety A: A, which is a moiety of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   each instance of R¹ independently is —H or a C₁-C₂₀ aliphatic        group;    -   each instance of R² independently is —H or a C₁-C₂₀ aliphatic        group;    -   each instance of R³ independently is —H or a C₁-C₂₀ aliphatic        group;    -   X is independently S or O;    -   n1 is an integer from 1 to 6;    -   n2 is an integer from 1 to 6;    -   R is N or CH; and    -   L is C₁₋₆ alkyl or a protonatable group provided that when R is        CH then L is a protonatable group, wherein the protonatable        group comprises at least one 1° amino, 2° amino, 3° amino or        imidazolyl group.

In some embodiments, R¹ independently is —H, —CH₃, or —CH₂CH₃.

In some embodiments, R² independently is —H, —CH₃, or —CH₂CH₃.

In some embodiments, R³ independently is —H, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃,CH(CH₃)₂, or C(CH₃)₃.

In some embodiments, each instance of R¹ and R² independently is —H or—CH₃. In some embodiments, each instance of R¹ and R² is —H, —CH₃ or—CH₂CH₃. In some embodiments, each instance of R¹ and R² is —CH₃. Insome embodiments, each instance of R¹ and R² is —H.

In some embodiments, X is independently O.

In some embodiments, X is independently S.

In some embodiments, n1 is 1, 2 or 3; or n1 is 2, 3 or 4; or n1 is 3, 4or 5; or n1 is 4, 5 or 6; or n1 is 1 or 2; or n1 is 2 or 3; or n1 is 3or 4; or n1 is 4 or 5; or n1 is 5 or 6; or n1 is 1; or n1 is 2; or n1 is3; or n1 is 4; or n1 is 5; or n1 is 6.

In some embodiments, n2 is 1, 2 or 3; or n2 is 2, 3 or 4; or n2 is 3, 4or 5; or n2 is 4, 5 or 6; or n2 is 1 or 2; or n2 is 2 or 3; or n2 is 3or 4; or n2 is 4 or 5; or n2 is 5 or 6; or n2 is 1; or n2 is 2; or n2 is3; or n2 is 4; or n2 is 5; or n2 is 6.

In some embodiments,

-   n1 is 1, 2 or 3; or n1 is 2, 3 or 4; or n1 is 3, 4 or 5; or n1 is 4,    5 or 6; or n1 is 1 or 2; or n1 is 2 or 3; or n1 is 3 or 4; or n1 is    4 or 5; or n1 is 5 or 6; or n1 is 1; or n1 is 2; or n1 is 3; or n1    is 4; or n1 is 5; or n1 is 6;-   n2 is 1, 2 or 3; or n2 is 2, 3 or 4; or n2 is 3, 4 or 5; or n2 is 4,    5 or 6; or n2 is 1 or 2; or n2 is 2 or 3; or n2 is 3 or 4; or n2 is    4 or 5; or n2 is 5 or 6; or n2 is 1; or n2 is 2; or n2 is 3; or n2    is 4; or n2 is 5; or n2 is 6; and-   each instance of R¹ and R² independently is —H or —CH₃; or each    instance of R¹ and R² is —H, —CH₃ or —CH₂CH₃; or each instance of R¹    and R² is —CH₃; or each instance of R¹ and R² is —H.

In some embodiments, R is CH.

In some embodiments, R is N.

In some embodiments, R is N and L is C₁₋₆ alkyl.

In some embodiments, L is a protonatable group. A suitable protonatablegroup does not significantly interfere with the delivery of nucleic acidusing the polymer of the present invention. Generally, a suitableprotonatable group is a C₁₋₁₀ hydrocarbon additionally containing atleast one 1° amino, 2° amino, 3° amino or imidazolyl group. In someembodiments, non-protonatable linkages such as esters and ethers mayalso be present. In some embodiments, sidechains of the naturallyoccurring amino acids may also be present.

In some embodiments, L is a protonatable group such that at least oneconjugate acid of L-H has a pKa in water of about 4.5 to about 11.5. Insome embodiments, L is a protonatable group such that at least oneconjugate acid of L-H has a pKa in water of about 5 to about 11. In someembodiments, L is a protonatable group such that at least one conjugateacid of L-H has a pKa in water of about 6 to about 10. In someembodiments, L is a protonatable group such that at least one conjugateacid of L-H has a pKa in water of about 7 to about 9. In someembodiments, L is a protonatable group such that at least one conjugateacid of L-H has a pKa in water of about 8. In some embodiments, L is aprotonatable group such that at least one conjugate acid of L-H has apKa in water of 10.

In some embodiments, L is a protonatable group such that at least oneconjugate acid of L-H has a pKa in water of about 5 to about 7. In someembodiments, L is a protonatable group such that at least one conjugateacid of L-H has a pKa in water of about 6 or 7. In some embodiments, Lis a protonatable group such that at least one conjugate acid of L-H hasa pKa in water of about 8 to about 11. In some embodiments, L is aprotonatable group such that at least one conjugate acid of L-H has apKa in water of about 9 or 10. In some embodiments, L is a protonatablegroup such that at least one conjugate acid of L-H has a pKa in water ofabout 8.

In some embodiments, R is CH and L is a protonatable group. In someembodiments, R is N and L is a protonatable group.

In some embodiments, the moiety A:

A is a moiety of formula (II):

or a pharmaceutically acceptable salt thereof, wherein:

-   L is C₁₋₆ alkyl; and-   each of R, R¹, R², R³, X, n1 and n2 is as defined above for formula    (I), both singly and in combination.

In some embodiments, L is —CH₃, Et, Pr, ^(i)Pr, Bu, sec-Bu, ^(i)Bu,tert-Bu, pentyl, tert-pentyl, isopentyl, sec-pentyl, 3-pentyl or hexyl.In some embodiments, L is —CH₃, Et, Pr, ^(i)Pr or Bu. In someembodiments, L is —CH₃, Et or Pr. In some embodiments, L is —CH₃. Insome embodiments, L is Et. In some embodiments, L is Pr. In someembodiments, L is ^(i)Pr. In some embodiments, L is Bu.

In some embodiments, the moiety A of formula (II) is a moiety of formula(IIa):

-   wherein each of R¹, R², R³, X, L, n1 and n2 is as defined and    described in embodiments of formula (II), above, both singly and in    combination.

In some embodiments, the moiety A of formula (II) is a moiety of formula(IIb):

-   wherein each of R¹, R², R³, X, L, n1 and n2 is as defined and    described in embodiments of formula (II), above, both singly and in    combination.

In some embodiments, the moiety A:

A is a moiety of formula (III):

-   or a pharmaceutically acceptable salt thereof, wherein:-   each of R⁴ and R⁵ independently is —H or a C₁-C₂₀ aliphatic group    (e.g., a C₁₋₆ alkyl); and-   each of R, R¹, R², R³, X, n1 and n2 is as defined above for formula    (I), both singly and in combination.

In some embodiments, R⁴ independently is —H, —CH₃, Et, Pr, ^(i)Pr, Bu,sec-Bu, ^(i)Bu, tert-Bu, pentyl, tert-pentyl, isopentyl, sec-pentyl,3-pentyl or hexyl; or R⁴ is —H, —CH₃, Et, Pr, ^(i)Pr or Bu; or R⁴ is—CH₃, Et, Pr, ^(i)Pr or Bu; or R⁴ is —H, —CH₃, Et or Pr; or R⁴ is —CH₃,Et or Pr; or R⁴ is —CH₃; or R⁴ is Et; or R⁴ is Pr.

In some embodiments, R⁵ independently is —H, —CH₃, Et, Pr, ^(i)Pr, Bu,sec-Bu, ^(i)Bu, tert-Bu, pentyl, tert-pentyl, isopentyl, sec-pentyl,3-pentyl or hexyl; or R⁵ is —CH₃, Et, Pr, ^(i)Pr, Bu, sec-Bu, ^(i)Bu,tert-Bu, pentyl, tert-pentyl, isopentyl, sec-pentyl, 3-pentyl or hexyl;or R⁵ is —CH₃, Et, Pr, ^(i)Pr or Bu; or R⁴ is —CH₃, Et or Pr; or R⁵ is—CH₃; or R⁵ is Et; or R⁵ is Pr.

In some embodiments, R⁴ is —H, —CH₃, Et, Pr, ^(i)Pr, Bu, sec-Bu, ^(i)Bu,tert-Bu, pentyl, tert-pentyl, isopentyl, sec-pentyl, 3-pentyl or hexyl.In some embodiments, R⁴ is —H, —CH₃, Et, Pr, ^(i)Pr or Bu. In someembodiments, R⁴ is —CH₃, Et, Pr, ^(i)Pr or Bu. In some embodiments, R⁴is —H, —CH₃, Et or Pr. In some embodiments, R⁴ is —CH₃, Et or Pr. Insome embodiments, R⁴ is —CH₃. In some embodiments, R⁴ is Et. In someembodiments, R⁴ is Pr.

In some embodiments, R⁵ is —H, —CH₃, Et, Pr, ^(i)Pr, Bu, sec-Bu, ^(i)Bu,tert-Bu, pentyl, tert-pentyl, isopentyl, sec-pentyl, 3-pentyl or hexyl.In some embodiments, R⁵ is —CH₃, Et, Pr, ^(i)Pr or Bu. In someembodiments, R⁵ is —CH₃, Et or Pr. In some embodiments, R⁵ is —CH₃. Insome embodiments, R⁵ is Et. In some embodiments, R⁵ is Pr.

In some embodiments, the moiety A of formula (III) is a moiety offormula (IIIa):

-   wherein each of R¹, R², R³, R⁴, R⁵, X, n1 and n2 is as defined and    described in embodiments of formula (III), above, both singly and in    combination.

In some embodiments, the moiety A of formula (III) is a moiety offormula (IIIb):

-   wherein each of R¹, R², R³, R⁴, R⁵, X, n1 and n2 is as defined and    described in embodiments of formula (III), above, both singly and in    combination.

In some embodiments, the moiety A:

A is a moiety of formula (IV):

-   or a pharmaceutically acceptable salt thereof, wherein:-   n3 is 1, 2, 3 or 4;-   R⁷ is halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, —OH, —OR^(J1), —NH₂,    —NHR^(J1), —N(R^(J1))₂, —C(O)R^(J1), —CN or —NO₂, wherein each    instance of R¹¹ is independently C₁₋₃ alkyl;-   R⁶ is —H or a C₁-C₂₀ aliphatic group (e.g., a C₁₋₆ alkyl); and-   each of R, R¹, R², R³, X, n1, and n2 is as defined above for formula    (I), both singly and in combination.

In some embodiments, R⁶ is —H, —CH₃, Et, Pr, ^(i)Pr, Bu, sec-butyl,^(i)Bu, tert-Bu, pentyl, tert-pentyl, isopentyl, sec-pentyl, 3-pentyl,or hexyl; or R⁶ is —CH₃, Et, Pr, ^(i)Pr, Bu, sec-butyl, ^(i)Bu, tert-Bu,pentyl, tert-pentyl, isopentyl, sec-pentyl, 3-pentyl, or hexyl; or R⁶ is—CH₃, Et, Pr, ^(i)Pr, or Bu; or R⁶ is —CH₃, Et, or Pr; or R⁶ is —CH₃.

In some embodiments, R⁷ is —H, —CH₃, Et, Pr, Bu, —NH₂, —NHMe, —NMe₂,—NHEt or —NEt₂; or R⁷ is —H, —CH₃, Et, Pr, —NH₂, —NHMe or —NMe₂; or R⁷is —CH₃, Et or Pr; or R⁷ is Pr.

In some embodiments, n3 is 1, 2 or 3; or n3 is 2, 3 or 4; or n3 is 2 or3; or n3 is 2; or n3 is 3.

In some embodiments, R⁶ is —H, —CH₃, Et, Pr, ^(i)Pr, Bu, sec-butyl,^(i)Bu, tert-Bu, pentyl, tert-pentyl, isopentyl, sec-pentyl, 3-pentyl,or hexyl. In some embodiments, R⁶ is —CH₃, Et, Pr, ^(i)Pr, Bu,sec-butyl, ^(i)Bu, tert-Bu, pentyl, tert-pentyl, isopentyl, sec-pentyl,3-pentyl, or hexyl. In some embodiments, R⁶ is —CH₃, Et, Pr, ^(i)Pr, orBu. In some embodiments, R⁶ is —CH₃, Et, or Pr. In some embodiments, R⁶is —CH₃.

In some embodiments, R⁷ is —H, —CH₃, Et, Pr, Bu, —NH₂, —NHMe, —NMe₂,—NHEt or —NEt₂. In some embodiments, R⁷ is —H, —CH₃, Et, Pr, —NH₂, —NHMeor —NMe₂. In some embodiments, R⁷ is —CH₃, Et or Pr. In someembodiments, R⁷ is Pr.

In some embodiments, n3 is 1, 2 or 3. In some embodiments, n3 is 2, 3 or4. In some embodiments, n3 is 2 or 3. In some embodiments, n3 is 2. Insome embodiments, n3 is 3.

In some embodiments, the moiety A of formula (IV) is a moiety of formula(IVa):

-   wherein each of R¹, R², R³, R⁶, R⁷, X, n1, n2 and n3 is as defined    and described in embodiments of formula (IV), above, both singly and    in combination.

In some embodiments, the moiety A of formula (IV) is a moiety of formula(IVb):

-   wherein each of R¹, R², R³, R⁶, R⁷, X, n1, n2, and n3 is as defined    and described in embodiments of formula (IV), above, both singly and    in combination.

In some embodiments, the moiety A

A is a moiety of formula (V):

-   or a pharmaceutically acceptable salt thereof, wherein:-   each of R⁸, R⁹, R¹⁰ and R¹¹ independently is a C₁-C₂₀ aliphatic    (e.g., a C₁₋₆ aliphatic, C₁₋₄ haloalkyl or C₃₋₆ cycloalkyl, each of    which is optionally substituted with 1-4 occurrences of R*);-   each instance of R* independently is halogen, —CO₂R^(J1), —CN, —OH,    —OR^(J1), —NH₂, —NHR^(J1), —N(R^(J1))₂, —SR^(J1) or —SO₂R^(J1),    wherein each instance of R^(J1) independently is C₁₋₃ alkyl; and-   each of R¹, R², R³, X, n1 and n2 is as defined above for formula    (I), both singly and in combination.

In some embodiments, R⁸ is —H, —CH₃, Et, Pr, Bu, —(CH₂)₃NH₂, —(CH₂)₄NH₂or —(CH₂)₅NH₂; or R⁸ is —H, —CH₃, Et, —(CH₂)₄NH₂, or —(CH₂)₅NH₂; or R⁸is —H or —(CH₂)₄NH₂; or R⁸ is —(CH₂)₄NH₂.

In some embodiments, R⁹ is —H, —CH₃, Et, Pr, Bu, —NH₂, —NHMe, —NMe₂,—NHEt or —NEt₂; or R⁹ is —H, —CH₃, Et, Pr, —NH₂, —NHMe or —NMe₂; or R⁹is —CH₃, Et or Pr; or R⁹ is Pr.

In some embodiments, R¹⁰ is —CH₃, Et, Pr, ^(i)Pr, Bu, sec-butyl, ^(i)Bu,tert-Bu, pentyl, tert-pentyl, isopentyl, sec-pentyl, 3-pentyl or hexyl;or R¹⁰ is —CH₃, Et, Pr, ^(i)Pr or Bu; or R¹⁰ is —CH₃, Et or Pr; or R¹⁰is —CH₃.

In some embodiments, R¹¹ is —H, —CH₃, Et, Pr, ^(i)Pr, Bu, hexyl,cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or R¹¹ is H, —CH₃,Et, Pr or cyclopropyl; or R¹¹ is H, —CH₃ or Et; or R¹¹ is —H.

In some embodiments, R⁸ is —H, —CH₃, Et, Pr, Bu, —(CH₂)₃NH₂, —(CH₂)₄NH₂or —(CH₂)₅NH₂. In some embodiments, R⁸ is —H, —CH₃, Et, —(CH₂)₄NH₂, or—(CH₂)₅NH₂. In some embodiments, R⁸ is —H or —(CH₂)₄NH₂. In someembodiments, R⁸ is —(CH₂)₄NH₂.

In some embodiments, R⁹ is —H, —CH₃, Et, Pr, Bu, —NH₂, —NHMe, —NMe₂,—NHEt or —NEt₂. In some embodiments, R⁹ is —H, —CH₃, Et, Pr, —NH₂, —NHMeor —NMe₂. In some embodiments, R⁹ is —CH₃, Et or Pr. In someembodiments, R⁹ is Pr.

In some embodiments, R¹⁰ is —CH₃, Et, Pr, ^(i)Pr, Bu, sec-butyl, ^(i)Bu,tert-Bu, pentyl, tert-pentyl, isopentyl, sec-pentyl, 3-pentyl or hexyl.In some embodiments, R¹⁰ is —CH₃, Et, Pr, ^(i)Pr or Bu. In someembodiments, R¹⁰ is —CH₃, Et or Pr. In some embodiments, R¹⁰ is —CH₃.

In some embodiments, R¹¹ is —H, —CH₃, Et, Pr, ^(i)Pr, Bu, hexyl,cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments,R¹¹ is H, —CH₃, Et, Pr or cyclopropyl. In some embodiments, R¹¹ is H,—CH₃ or Et. In some embodiments, R¹¹ is —H.

In some embodiments, the moiety A of formula (V) is a moiety of formula(Va):

-   wherein each of R¹, R, R³, R⁸, R⁹, R¹⁰, R¹¹, X, n1 and n2 is as    defined and described in embodiments of formula (V), above, both    singly and in combination.

In some embodiments, the moiety A of formula (V) is a moiety of formula(Vb):

-   wherein each of R¹, R², R³, R⁸, R⁹, R¹⁰, R¹¹, X, n1 and n2 is as    defined and described in embodiments of formula (V), above, both    singly and in combination.

In some embodiments, the moiety A:

A is a moiety of formula (VI):

-   or a pharmaceutically acceptable salt thereof, wherein:-   B is a 5-membered heterocycle having 1 or 2 ring nitrogen atoms;-   n4 is 1, 2, 3 or 4;-   each instance of R¹² independently is selected from halo, C₁₋₄    alkyl, C₁₋₄ haloalkyl, —OH, —OR^(J1), —NH₂,    -   —NHR^(J1), —N(R^(J1))₂, —C(O)R^(J1), —CN and —NO₂;    -   wherein each instance of R^(J1) is independently C₁₋₃ alkyl;-   n5 is 0, 1, 2 or 3; and-   each of R, R¹, R², R³, X, n1 and n2 is as defined above in formula    (I), both singly and in combination.

In some embodiments, B is an aromatic heterocyclic ring.

In some embodiments, B is a non-aromatic heterocyclic ring.

In some embodiments, B is pyrazolyl, imidazolyl, pyrrolyl, triazolyl, ortertazolyl; or B is pyrazolyl or imidazolyl; or B is imidazolyl.

In some embodiments, R¹² is —CH₃, Et, Pr, Bu, ^(i)Pr, —F, —Cl, —CF₃,—OMe, —OEt, —OPr, —NH₂, —SO₂NH₂, —CN or —NO₂; or R¹² is —CH₃, —F, —Cl,—CF₃, —OMe or —OEt; or R¹² is —F, —CH₃ or —Cl; or R¹² is —CH₃.

In some embodiments, n4 is 0, 1 or 2; or n4 is 0 or 1; or n4 is 0.

In some embodiments, n5 is 0, 1 or 2; or n5 is 0 or 1; or n5 is 0.

In some embodiments, B is pyrazolyl, imidazolyl, pyrrolyl, triazolyl, ortertazolyl. In some embodiments, B is pyrazolyl or imidazolyl. In someembodiments, B is imidazolyl.

In some embodiments, R¹² is —CH₃, Et, Pr, Bu, ^(i)Pr, —F, —Cl, —CF₃,—OMe, —OEt, —OPr, —NH₂, —SO₂NH₂, —CN or —NO₂. In some embodiments, R¹²is —CH₃, —F, —Cl, —CF₃, —OMe or —OEt. In some embodiments, R¹² is —F,—CH₃ or —Cl. In some embodiments, R¹² is —CH₃.

In some embodiments, n4 is 0, 1 or 2. In some embodiments, n4 is 0 or 1.In some embodiments, n4 is 0.

In some embodiments, n5 is 0, 1 or 2. In some embodiments, n5 is 0 or 1.In some embodiments, n5 is 0.

In some embodiments, n5 is 0, 1, or 2; and R¹² is —F or —CH₃. In someembodiments, n5 is 1 and R¹² is —CH₃.

In some embodiments, the moiety A of formula (VI) is a moiety of formula(VIa):

-   wherein each of R¹, R², R³, R¹², B, X, n1, n2, n4 and n5 is as    defined and described in embodiments of formula (VI), above, both    singly and in combination.

In some embodiments, the moiety A of formula (VI) is a moiety of formula(VIb):

-   wherein each of R¹, R², R³, R¹², X, B, n1, n2, n4 and n5 is as    defined and described in embodiments of formula (VI), above, both    singly and in combination.

In some embodiments, the moiety A:

A is a moiety of formula (VII):

-   or a pharmaceutically acceptable salt thereof, wherein:-   X′ is —O— or —NR¹³—, wherein    -   R¹³ is —H or a C₁-C₂₀ aliphatic (e.g., a C₁₋₆ aliphatic or C₃₋₆        cycloalkyl);-   n4 is 0, 1, 2 or 3;-   each of R⁸, R⁹ and R¹⁰ is —H or is a C₁-C₂₀ aliphatic (e.g., a C₁₋₆    aliphatic, C₁₋₄ haloalkyl or C₃₋₆ cycloalkyl, each of which is    optionally substituted with 1-4 occurrences of R*);-   each instance of R* independently is halogen, —CO₂R^(J1), —CN, —OH,    —OR^(J1), —NH₂, —NHR^(J1), —N(R^(J1))₂, —SR^(J1) or —SO₂R^(J1),    -   wherein each instance of R¹¹ independently is C₁₋₃ alkyl; and-   each of R, R¹, R², R³, X, n1 and n2 is as defined above in formula    (I), both singly and in combination.

In some embodiments, X′ is —NH— or —O—; or X′ is —NR¹³—; or X′ is —NH—;or X′ is —O—.

In some embodiments, n4 is 1, 2 or 3; or n4 is 1 or 2; or n4 is 2 or 3;or n4 is 1.

In some embodiments, R⁸ is —H, —CH₃, Et, Pr, Bu, —NH₂, —NHMe, —NMe₂,—NHEt or —NEt₂; or R⁸ is —H, —CH₃, Et, Pr, —NH₂, —NHMe or —NMe₂; or R⁸is —CH₃, Et or Pr; or R⁸ is Pr.

In some embodiments, R⁹ is —H, —CH₃, Et, Pr, ^(i)Pr, Bu, sec-butyl,^(i)Bu, tert-Bu, pentyl, tert-pentyl, isopentyl, sec-pentyl, 3-pentyl orhexyl; or R⁹ is —CH₃, Et, Pr, ^(i)Pr, Bu, sec-butyl, ^(i)Bu, tert-Bu,pentyl, tert-pentyl, isopentyl, sec-pentyl, 3-pentyl or hexyl; or R⁹ is—CH₃, Et, Pr, ^(i)Pr or Bu; or R⁹ is —CH₃, Et or Pr; or R⁹ is —CH₃.

In some embodiments, R¹⁰ is —H, —CH₃, Et, Pr, Bu, —(CH₂)₃NH₂, —(CH₂)₄NH₂or —(CH₂)₅NH₂; or R¹⁰ is —H, —CH₃, Et, —(CH₂)₄NH₂ or —(CH₂)₅NH₂; or R¹⁰is —H or —(CH₂)₄NH₂; or R¹⁰ is —(CH₂)₄NH₂.

In some embodiments, R¹³ is —H, —CH₃, Et, Pr, ^(i)Pr, Bu, hexyl,cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or R¹³ is —H, —CH₃,Et, cyclopropyl or cyclobutyl; or R¹³ is —H, —CH₃ or cyclopropyl; or R¹³is —H.

In some embodiments, X′ is —NH— or —O—. In some embodiments, X′ is—NR¹³. In some embodiments, X′ is —NH—. In some embodiments, X′ is —O—.

In some embodiments, n4 is 1, 2 or 3. In some embodiments, n4 is 1 or 2.In some embodiments, n4 is 2 or 3. In some embodiments, n4 is 1.

In some embodiments, R⁸ is —H, —CH₃, Et, Pr, Bu, —NH₂, —NHMe, —NMe₂,—NHEt or —NEt₂. In some embodiments, R⁸ is —H, —CH₃, Et, Pr, —NH₂, —NHMeor —NMe₂. In some embodiments, R⁸ is —CH₃, Et or Pr. In someembodiments, R⁸ is Pr.

In some embodiments, R⁹ is —H, —CH₃, Et, Pr, ^(i)Pr, Bu, sec-butyl,^(i)Bu, tert-Bu, pentyl, tert-pentyl, isopentyl, sec-pentyl, 3-pentyl orhexyl. In some embodiments, R⁹ is —CH₃, Et, Pr, ^(i)Pr, Bu, sec-butyl,^(i)Bu, tert-Bu, pentyl, tert-pentyl, isopentyl, sec-pentyl, 3-pentyl orhexyl. In some embodiments, R⁹ is —CH₃, Et, Pr, ^(i)Pr or Bu. In someembodiments, R⁹ is —CH₃, Et or Pr. In some embodiments, R⁹ is —CH₃.

In some embodiments, R¹⁰ is —H, —CH₃, Et, Pr, Bu, —(CH₂)₃NH₂, —(CH₂)₄NH₂or —(CH₂)₅NH₂. In some embodiments, R¹⁰ is —H, —CH₃, Et, —(CH₂)₄NH₂ or—(CH₂)₅NH₂. In some embodiments, R¹⁰ is —H or —(CH₂)₄NH₂. In someembodiments, R¹⁰ is —(CH₂)₄NH₂.

In some embodiments, R¹³ is —H, —CH₃, Et, Pr, ^(i)Pr, Bu, hexyl,cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments,R¹³ is —H, —CH₃, Et, cyclopropyl or cyclobutyl. In some embodiments, R¹³is —H, —CH₃ or cyclopropyl. In some embodiments, R¹³ is —H.

In some embodiments, the moiety A of formula (VII) is a moiety offormula (VIIa):

-   wherein each of R¹, R², R³, R⁹, R¹⁰, n1, n2, X, and X′ is as defined    and described in embodiments of formula (VII), above, and in    embodiments of formula (VIIa), below, both singly and in    combination.

In some embodiments, R⁹ is —H, —CH₃, Et, Pr, Bu, —NH₂, —NHMe, —NMe₂,—NHEt or —NEt₂. In some embodiments, R⁹ is —H, —CH₃, Et, Pr, —NH₂, —NHMeor —NMe₂. In some embodiments, R⁹ is —CH₃, Et or Pr. In someembodiments, R⁹ is Pr.

In some embodiments, R¹⁰ is —CH₃, Et, Pr, ^(i)Pr, Bu, sec-butyl, ^(i)Bu,tert-Bu, pentyl, tert-pentyl, isopentyl, sec-pentyl, 3-pentyl or hexyl.In some embodiments, R¹⁰ is —CH₃, Et, Pr, ^(i)Pr or Bu. In someembodiments, R¹⁰ is —CH₃, Et, or Pr. In some embodiments, R¹⁰ is —CH₃.

In some embodiments, the moiety A of formula (VII) is a moiety offormula (VIIb):

-   wherein each of R¹, R², R³, R⁹, R¹⁰, n1, n2, X, and X′ is as defined    and described in embodiments of formula (VII), above, and in    embodiments of formula (VIIb), below, both singly and in    combination.

In some embodiments, R⁹ is —H, —CH₃, Et, Pr, Bu, —NH₂, —NHMe, —NMe₂,—NHEt or —NEt₂. In some embodiments, R⁹ is —H, —CH₃, Et, Pr, —NH₂, —NHMeor —NMe₂. In some embodiments, R⁹ is —CH₃, Et or Pr. In someembodiments, R⁹ is Pr.

In some embodiments, R¹⁰ is —CH₃, Et, Pr, ^(i)Pr, Bu, sec-butyl, ^(i)Bu,tert-Bu, pentyl, tert-pentyl, isopentyl, sec-pentyl, 3-pentyl or hexyl.In some embodiments, R¹⁰ is —CH₃, Et, Pr, ^(i)Pr or Bu. In someembodiments, R¹⁰ is —CH₃, Et, or Pr. In some embodiments, R¹⁰ is —CH₃.

In some embodiments, a the moiety A of formula (VII) is a moiety offormula (VIIc):

-   wherein each of R¹, R², R³, R⁸, R⁹, R¹⁰, n1, n2, X, and X′ is as    defined and described in embodiments of formula (VII), above, and in    embodiments of formula (VIIc), below, both singly and in    combination.

In some embodiments, R⁸ is —H, —CH₃, Et, Pr, Bu, —NH₂, —NHMe, —NMe₂,—NHEt or —NEt₂. In some embodiments, R⁸ is —H, —CH₃, Et, Pr, —NH₂, —NHMeor —NMe₂. In some embodiments, R⁸ is —CH₃, Et or Pr. In someembodiments, R⁸ is Pr.

In some embodiments, R⁹ is —H, —CH₃, Et, Pr, ^(i)Pr, Bu, sec-butyl,^(i)Bu, tert-Bu, pentyl, tert-pentyl, isopentyl, sec-pentyl, 3-pentyl orhexyl. In some embodiments, R⁹ is —CH₃, Et, Pr, ^(i)Pr, Bu, sec-butyl,^(i)Bu, tert-Bu, pentyl, tert-pentyl, isopentyl, sec-pentyl, 3-pentyl orhexyl. In some embodiments, R⁹ is —CH₃, Et, Pr, ^(i)Pr or Bu. In someembodiments, R⁹ is —CH₃, Et or Pr. In some embodiments, R⁹ is —CH₃.

In some embodiments, R¹⁰ is —H, —CH₃, Et, Pr, Bu, —(CH₂)₃NH₂, —(CH₂)₄NH₂or —(CH₂)₅NH₂. In some embodiments, R¹⁰ is —H, —CH₃, Et, —(CH₂)₄NH₂ or—(CH₂)₅NH₂. In some embodiments, R¹⁰ is —H or —(CH₂)₄NH₂. In someembodiments, R¹⁰ is —(CH₂)₄NH₂.

In some embodiments, the moiety A of formula (VII) is a moiety offormula (VIId):

-   wherein each of R¹, R², R³, R⁹, R¹⁰, R¹³, X, n1, and n2 is as    defined and described in embodiments of formula (VII), above, and in    embodiments of formula (VIId), below, both singly and in    combination.

In some embodiments, R⁹ is —H, —CH₃, Et, Pr, Bu, —NH₂, —NHMe, —NMe₂,—NHEt or —NEt₂. In some embodiments, R⁹ is —H, —CH₃, Et, Pr, —NH₂, —NHMeor —NMe₂. In some embodiments, R⁹ is —CH₃, Et or Pr. In someembodiments, R⁹ is Pr.

In some embodiments, R¹⁰ is —CH₃, Et, Pr, ^(i)Pr, Bu, sec-butyl, ^(i)Bu,tert-Bu, pentyl, tert-pentyl, isopentyl, sec-pentyl, 3-pentyl or hexyl.In some embodiments, R¹⁰ is —CH₃, Et, Pr, ^(i)Pr or Bu. In someembodiments, R¹⁰ is —CH₃, Et, or Pr. In some embodiments, R¹⁰ is —CH₃.

In some embodiments, R¹³ is —H, —CH₃, Et, Pr, ^(i)Pr, Bu, hexyl,cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments,R¹³ is —H, —CH₃, Et, cyclopropyl or cyclobutyl. In some embodiments, R¹³is —H, —CH₃ or cyclopropyl. In some embodiments, R¹³ is —H.

In some embodiments, the moiety A:

A is a moiety of formula (VIII):

-   or a pharmaceutically acceptable salt thereof, wherein:-   R¹⁴ is a side chain of an amino acid (e.g., a naturally-occurring    amino acid);-   n4 is 0, 1, 2 or 3;-   each of R⁹ and R¹⁰ is —H or is a C₁-C₂₀ aliphatic (e.g., a C₁₋₆    aliphatic, C₁₋₄ haloalkyl or C₃₋₆ cycloalkyl, each of which is    optionally substituted with 1-4 occurrences of R*).-   each instance of R* independently is halogen, —CO₂R^(J1), —CN, —OH,    —OR^(J1), —NH₂, —NHR^(J1), —N(R^(J1))₂, —SR^(J1) or —SO₂R^(J1),    -   wherein each instance of R¹ independently is C₁₋₃ alkyl; and-   each of R, R¹, R², R³, X, n1 and n2 is as defined above in formula    (I), both singly and in combination.

In some embodiments, n4 is 1, 2 or 3; or n4 is 1 or 2; or n4 is 2 or 3;or n4 is 1.

In some embodiments, R⁹ is —H, —CH₃, Et, Pr, Bu, —NH₂, —NHMe, —NMe₂,—NHEt, or —NEt₂; or R⁹ is —H, —CH₃, Et, Pr, —NH₂, —NHMe, or —NMe₂; or R⁹is —CH₃, Et, or Pr; or R⁹ is Pr.

In some embodiments, R¹⁰ is —CH₃, Et, Pr, ^(i)Pr, Bu, sec-butyl, ^(i)Bu,tert-Bu, pentyl, tert-pentyl, isopentyl, sec-pentyl, 3-pentyl or hexyl;or R¹⁰ is —CH₃, Et, Pr, ^(i)Pr or Bu; or R¹⁰ is —CH₃, Et or Pr; or R¹⁰is —CH₃.

In some embodiments, R¹⁴ is a side chain of alanine, valine, leucine,isoleucine, methionine, phenylalanine, tryptophan, proline, serine,threonine, cysteine, tyrosine, asparagine, lysine, arginine orhistidine; or R¹⁴ is a side chain of tryptophan, proline, serine,threonine, cysteine, tyrosine, asparagine, lysine, arginine orhistidine; or R¹⁴ is a side chain of lysine or histidine.

In some embodiments, n4 is 1, 2 or 3. In some embodiments, n4 is 1 or 2.In some embodiments, n4 is 2 or 3. In some embodiments, n4 is 1.

In some embodiments, R⁹ is —H, —CH₃, Et, Pr, Bu, —NH₂, —NHMe, —NMe₂,—NHEt, or —NEt₂. In some embodiments, R⁹ is —H, —CH₃, Et, Pr, —NH₂,—NHMe, or —NMe₂. In some embodiments, R⁹ is —CH₃, Et, or Pr. In someembodiments, R⁹ is Pr.

In some embodiments, R¹⁰ is —CH₃, Et, Pr, ^(i)Pr, Bu, sec-butyl, ^(i)Bu,tert-Bu, pentyl, tert-pentyl, isopentyl, sec-pentyl, 3-pentyl or hexyl.In some embodiments, R¹⁰ is —CH₃, Et, Pr, ^(i)Pr or Bu. In someembodiments, R¹⁰ is —CH₃, Et or Pr. In some embodiments, R¹⁰ is —CH₃.

In some embodiments, R¹⁴ is a side chain of alanine, valine, leucine,isoleucine, methionine, phenylalanine, tryptophan, proline, serine,threonine, cysteine, tyrosine, asparagine, lysine, arginine orhistidine. In some embodiments, R¹⁴ is a side chain of tryptophan,proline, serine, threonine, cysteine, tyrosine, asparagine, lysine,arginine or histidine. In some embodiments, R¹⁴ is a side chain oflysine or histidine.

In some embodiments, R¹⁴ is —H, —CH₃, ^(i)Pr, ^(i)Bu, sec-butyl, —CH₂OH,—CH₂SH,

In some embodiments, R¹⁴ is —CH₂SH, —CH₂OH,

In some embodiments, R¹⁴ is

In some embodiments, the moiety A of formula (VIII) is a moiety offormula (VIIIa):

-   wherein each of R¹, R², R³, R⁹, R¹⁰, R¹⁴, X, n1, and n2 is as    defined and described in embodiments of formula (VIII), above, both    singly and in combination.

In some embodiments, the moiety A of formula (VIII) is a moiety offormula (VIIIb):

-   wherein each of R¹, R², R³, R⁹, R¹⁰, R¹⁴, X, n1, and n2 is as    defined and described in embodiments of formula (VIII), above, both    singly and in combination.

In some embodiments, the moiety A:

A is a moiety of formula (IX):

-   or a pharmaceutically acceptable salt thereof, wherein:-   X′ is —O— or —NR¹³—, wherein    -   R¹³ is —H, C₁₋₆ aliphatic or C₃₋₆ cycloalkyl;-   n4 is 0, 1, 2 or 3;-   R¹⁵ is —H or C₁₋₆alkyl;-   n6 is 1, 2, 3 or 4; and-   each of R, R¹, R², R³, X, n1 and n2 is as defined above in formula    (I), both singly and in combination.

In some embodiments, X is —O— or —NH—; or X is —O—; or X is —NH—.

In some embodiments, n4 is 1, 2 or 3; or n4 is 1 or 2; or n4 is 2 or 3;or n4 is 1.

In some embodiments, n6 is 1, 2, 3 or 4; or n6 is 2 or 3; or n6 is 2.

In some embodiments, R¹⁵ is —H, —CH₃, Et, Pr, ^(i)Pr, Bu, sec-butyl,^(i)Bu, tert-Bu, pentyl, tert-pentyl, isopentyl, sec-pentyl, 3-pentyl orhexyl; or R¹⁵ is —H, —CH₃, Et, Pr, ^(i)Pr, or Bu; or R¹⁵ is —H, —CH₃, orEt, or Pr; or R¹⁵ is —H.

In some embodiments, X is —O— or —NH—. In some embodiments, X is —O—. Insome embodiments X is —NH—.

In some embodiments, n4 is 1, 2 or 3. In some embodiments, n4 is 1 or 2.In some embodiments, n4 is 2 or 3. In some embodiments, n4 is 1.

In some embodiments, n6 is 1, 2, 3 or 4. In some embodiments, n6 is 2 or3. In some embodiments n6 is 2.

In some embodiments, R¹⁵ is —H, —CH₃, Et, Pr, ^(i)Pr, Bu, sec-butyl,^(i)Bu, tert-Bu, pentyl, tert-pentyl, isopentyl, sec-pentyl, 3-pentyl orhexyl. In some embodiments, R¹⁵ is —H, —CH₃, Et, Pr, ^(i)Pr, or Bu. Insome embodiments, R¹⁵ is —H, —CH₃, or Et, or Pr. In some embodiments,R¹⁵ is —H.

In some embodiments, n6 is 2 or 3 and R¹⁵ is —H, —CH₃, Et or Pr. In someembodiments, n6 is 2 and R¹⁵ is —H or —CH₃. In some embodiments, n6 is 2and R¹⁵ is —H.

In some embodiments, the moiety A of formula (IX) is a moiety of formula(IXa):

-   wherein each of R¹, R², R³, R¹⁵, X, n1, n2 and n6 is as defined and    described in embodiments of formula (IX), above, both singly and in    combination.

In some embodiments, the moiety A of formula (IX) is a moiety of formula(IXb):

-   wherein each of R¹, R², R³, R¹⁵, X, n1, n2 and n6 is as defined and    described in embodiments of formula (IX), above, both singly and in    combination.

Examples of polymers of the present invention include those comprisingthe moiety A: A, which is a moiety of formula (I):

wherein:

-   -   each instance of R¹ independently is —H or a C₁-C₂₀ aliphatic        group;    -   each instance of R² independently is —H or a C₁-C₂₀ aliphatic        group;    -   each instance of R³ independently is —H or a C₁-C₂₀ aliphatic        group;    -   X is independently S or O;    -   n1 is an integer from 1 to 6;    -   n2 is an integer from 1 to 6; and

is any of the following:

In some embodiments, R¹ independently is —H, —CH₃ or —CH₂CH₃.

In some embodiments, R² independently is —H, —CH₃ or —CH₂CH₃.

In some embodiments, R³ independently is —H, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃,CH(CH₃)₂, or C(CH₃)₃.

In some embodiments, X is independently O.

In some embodiments, X is independently S.

Polymers

In some aspects, the present invention provides a polymer comprising themoiety A: A, which is a moiety of formula (I) as defined above (a“provided polymer”).

In some embodiments, a provided polymer is a homopolymer. In someembodiments, a provided homopolymer comprises the structure:

wherein m is an integer such that the weight average molecular weight(M_(w)) of the polymer is about 10 kDa to about 60 kDa.

In some embodiments, m is an integer such that M_(w) is about 10 kDa toabout 60 kDa, about 10 kDa to about 50 kDa, about 10 kDa to about 40kDa, about 10 kDa to about 30 kDa about 15 kDa to about 60 kDa, about 15kDa to about 50 kDa, about 15 kDa to about 40 kDa, or about 15 kDa toabout 30 kDa.

In some embodiments, the moiety:

constitutes at least 10%, at least 20%, at least 30%, at least 40%, atleast 50%, at least 60%, at least 65%, at least 70%, at least 75%, atleast 80%, at least 85%, at least 90% or at least 95% of the total M_(w)of the polymer.

In some embodiments, a provided polymer is a copolymer.

In some embodiments, a copolymer is a controlled di-block copolymer. Insome embodiments, a copolymer is a controlled tri-block copolymer. Insome embodiments, a copolymer is a mixed polymer. In some embodiments, acopolymer is an alternating copolymer. In some embodiments, a copolymeris a random copolymer. In some embodiments, a copolymer is a graftcopolymer. In some embodiments, a copolymer is a periodic copolymer. Insome embodiments, a copolymer is a statistical copolymer. In embodimentsa copolymer is linear. In some embodiments, a copolymer is a linearcopolymer. In some embodiments, a copolymer is a branched copolymer.

In some embodiments, a provided copolymer comprises two differentsegments:

-   m₁ instances of A and m₂ instances of B,-   wherein:-   A is a moiety of formula (I) as described above;-   B is a structurally distinct segment from A (e.g., B is a moiety of    formula (I) as described above but different from A); and-   m₁ and m₂ are integers such that the weight average molecular weight    (M_(w)) of the polymer is about 10 kDa to about 60 kDa.

In some embodiments, B is a moiety of formula (I) as described above butdifferent from A.

In some embodiments, B does not comprise any ionizable group. In someembodiments, B is neutral. In some embodiments, B is uncharged. In someembodiments, B is negatively charged. In some embodiments, B ispositively charged.

In some embodiments, B is a targeting group (e.g., a targeting group asdescribed herein).

In some embodiments, B is biodegradable. In embodiments, B isnon-biodegradable.

In some embodiments, B is a moiety that is a hydrocarbon (e.g., asaturated hydrocarbon or an unsaturated hydrocarbon).

In some embodiments, B is a moiety that is a lactide (e.g., L-lactide orD,L-lactide), glycolide, ethylene glycol, caprolactone, propylenefumarate, or a 2-oxazoline.

In some embodiments, m₁ and m₂ are integers such that M_(w) is about 10kDa to about 60 kDa, about 10 kDa to about 50 kDa, about 10 kDa to about40 kDa, about 10 kDa to about 30 kDa about 15 kDa to about 60 kDa, about15 kDa to about 50 kDa, about 15 kDa to about 40 kDa, or about 15 kDa toabout 30 kDa.

In some embodiments, the

m₁ instances of A and m₂ instances of Btogether constitute at least 10%, at least 20%, at least 30%, at least40%, at least 50%, at least 60%, at least 65%, at least 70%, at least75%, at least 80%, at least 85%, at least 90% or at least 95% of thetotal M_(w) of the polymer.

In some embodiments, a provided copolymer is an alternating copolymer.In some embodiments, a provided alternating copolymer comprises thestructure:

wherein m′ is an integer such that the weight average molecular weight(M_(w)) of the polymer is about 10 kDa to about 60 kDa.

In some embodiments, m′ is an integer such that M_(w) is about 10 kDa toabout 60 kDa, about 10 kDa to about 50 kDa, about 10 kDa to about 40kDa, about 10 kDa to about 30 kDa about 15 kDa to about 60 kDa, about 15kDa to about 50 kDa, about 15 kDa to about 40 kDa, or about 15 kDa toabout 30 kDa.

In some embodiments, the moiety:

constitutes at least 10%, at least 20%, at least 30%, at least 40%, atleast 50%, at least 60%, at least 65%, at least 70%, at least 75%, atleast 80%, at least 85%, at least 90% or at least 95% of the total M_(w)of the polymer.

In some embodiments, a provided copolymer is an block copolymer. In someembodiments, a provided block copolymer comprises the structure:

wherein m₁ and m₂ are integers such that the weight average molecularweight (M_(w)) of the polymer is about 10 kDa to about 60 kDa.

In some embodiments, m₁ and m₂ are integers such that M_(w) is about 10kDa to about 60 kDa, about 10 kDa to about 50 kDa, about 10 kDa to about40 kDa, about 10 kDa to about 30 kDa about 15 kDa to about 60 kDa, about15 kDa to about 50 kDa, about 15 kDa to about 40 kDa, or about 15 kDa toabout 30 kDa.

In some embodiments, the moiety:

constitutes at least 10%, at least 20%, at least 30%, at least 40%, atleast 50%, at least 60%, at least 65%, at least 70%, at least 75%, atleast 80%, at least 85%, at least 90% or at least 95% of the total M_(w)of the polymer.

In some embodiments, a provided polymer comprises the moiety:

wherein:A is a moiety of formula (I) as described above; andT is a targeting group.

In embodiments, a provided polymer has hydrogen endgroups.

In embodiments, a provided polymer has oxygen-containing endgroups(e.g., hydroxyl or a C₁₋₆ alkoxyl).

In embodiments, a provided polymer has alkyl-containing endgroups (e.g.,a C₁₋₆ alkyl).

In some embodiments, the targeting group of a polymer is a moiety thatmay interact with a biological target of interest via a biologicalbinding event, i.e., between complementary pairs of biologicalmolecules. For example, a targeting group may comprise an entity such asbiotin that specifically binds to a complementary entity, such as avidinor streptavidin. Other examples of interactions that occur between pairsof biological molecules including proteins, nucleic acids,glycoproteins, carbohydrates, hormones, and the like. Specific examplesinclude an antibody/peptide pair, an antibody/antigen pair, an antibodyfragment/antigen pair, an antibody/antigen fragment pair, an antibodyfragment/antigen fragment pair, an antibody/hapten pair, anenzyme/substrate pair, an enzyme/inhibitor pair, an enzyme/cofactorpair, a protein/substrate pair, a nucleic acid/nucleic acid pair, aprotein/nucleic acid pair, a peptide/peptide pair, a protein/proteinpair, a small molecule/protein pair, a glutathione/GST pair, ananti-GFP/GFP fusion protein pair, a Myc/Max pair, a maltose/maltosebinding protein pair, a carbohydrate/protein pair, a carbohydratederivative/protein pair, a metal binding tag/metal/chelate, a peptidetag/metal ion-metal chelate pair, a peptide/NT A pair, alectin/carbohydrate pair, a receptor/hormone pair, a receptor/effectorpair, a complementary nucleic acid/nucleic acid pair, a ligand/cellsurface receptor pair, a virus/ligand pair, a Protein A/antibody pair, aProtein G/antibody pair, a Protein L/antibody pair, an Fereceptor/antibody pair, a biotin/avidin pair, a biotin/streptavidinpair, a drug/target pair, a zinc finger/nucleic acid pair, a smallmolecule/peptide pair, a small molecule/protein pair, a smallmolecule/target pair, a carbohydrate/protein pair such as maltose/MBP(maltose binding protein), a small molecule/target pair, or a metalion/chelating agent pair.

In some embodiments, the inclusion of a, S-acyl-2-thioethyl (SATE)protecting group is employed. Such a protecting group is readilycleavable through esterase enzymatic activity resulting in a liberatedphosphate functional group (Scheme 1). Upon cleavage of the SATE group,the generation of a negatively charged phosphate moiety is realized. Theresulting negative charge can counter-balance the cationic charge of theamino monomer moiety resulting in a zwitterionic region. Upon release ofsome SATE protecting groups, the polymer is partially neutralized,rendering its ability to bind nucleic acids diminished. Thus, partialrelease of the nucleic acid payload will occur. Upon release of all SATEprotecting groups, the polymer is completely neutralized, rendering itsability to bind nucleic acids removed. Thus, full release of the nucleicacid payload will occur. In total, such a polymer allows for facilecomplexation with nucleic acids, efficient release of payload andbiodegradability of itself.

In some embodiments, a branched poly(phosphoester) can be produced viareaction with any diol monomer with a reactive phosphate moiety withoutinclusion of the S-acyl-thioethanol group (Scheme 2). Further, a mixedbranched poly(phosphoester) polymer can be synthesized incorporatingboth the thioester functionality in selected ratios to afford partialbranching (Scheme 3).

Synthetic Methods

In general, the polymers of the invention can be prepared by methodsdescribed herein or by other methods known to those skilled in the art.Exemplary preparations of the polymers of the invention are describedbelow.

The following generic schemes and examples illustrate how to prepare thepolymers of the present disclosure. For example, stoichiometry of thereagents may be varied in order to obtain the desired monomer orpolymer.

As shown in pathway A in Scheme 4, above, the intermediate phosphatetriester 1.3 can be prepared, e.g., by treating p-nitrophenol withphosphoryl chloride (phosphorus oxychloride) in the presence of asuitable base such as triethylamine to produce intermediatephosphorochloridate 1.1, followed by treatment with S-(2-hydroxyethyl)ethanethioate in the presence of a suitable base such as triethylamine.Alternatively, as shown in pathway B, S-(2-hydroxyethyl) ethanethioatecan first be treated with phosphoryl chloride in the presence of, e.g.,a suitable base such as triethylamine to produce intermediate 1.2,followed by treatment with p-nitrophenol in the presence of a suitablebase such as triethylamine to yield phosphate triester 1.3.

As shown in Scheme 5, above, the intermediate phosphate triester 1.3 canbe converted to the moiety of Formula (I) by treatment with, e.g., anappropriately substituted diol 1.4 in the presence of (C) a suitablebase such as 1,8-diazabicyclo[5.4.0]undec-7-ene in a suitable solvent orcombination of solvents such as acetonitrile/dichloromethane or (D) asuitable Grignard reagent such as tert-butylmagnesium chloride in asuitable solvent such as tetrahydrofuran, followed by treatment with asuitable protic agent such as methanol.

Scheme 6, above, illustrates alternative routes to the moiety of Formula(I). For example, treatment of S-(2-hydroxyethyl) ethanethioate withN,N′-diisopropylphosphorodiamidic chloride in the presence of a suitablebase such as triethylamine in a suitable solvent such as diethyl etheryields the intermediate phosphorodiamidate 1.5. Subsequent treatmentwith an appropriately substituted diol 1.4 in the presence of a suitablebase such as nucleophilic catalysts or combinations thereof (e.g.,tetrazole and/or pyridine) yields the moiety of Formula (I).Alternatively, treatment of S-(2-hydroxyethyl) ethanethioate with1-chloro-N,N′-diisopropylphosphanediamine in the presence of a suitablebase such as triethylamine in a suitable solvent such as diethyl etheryields the intermediate alkoxyphosphanediamine 1.6. Subsequent treatmentwith an appropriately substituted diol 1.4 in the presence of a suitablenucleophilic catalyst such as tetrazole or pyridine followed by additionof a suitable oxidizing agent such as tert-butyl peroxide yields themoiety of Formula (I).

Scheme 7, above, illustrates another alternative route to the moiety ofFormula (I). Treatment of an appropriately substituted diol 1.4 withphosphoryl chloride (phosphorus oxychloride) in a suitable solvent suchas methylene chloride (dichloromethane) in the presence of a suitablebase such as triethylamine yields intermediate phosphorochloridate 1.7.Subsequent treatment of 1.7 with of S-(2-hydroxyethyl) ethanethioate ina suitable solvent such as tetrahydrofuran in the presence of a suitablebase such as triethylamine yields phosphate triester 1.8. Ring-openingpolymerization (ROP) of 1.8 yields the moiety of Formula (I).

Specific examples of poly(phosphoester) preparation are described in thefollowing paragraphs.

Nucleic Acids Synthesis of Nucleic Acids

Nucleic acids according to the present invention may be synthesizedaccording to any known methods. For example, mRNAs according to thepresent invention may be synthesized via in vitro transcription (IVT).Briefly, IVT is typically performed with a linear or circular DNAtemplate containing a promoter, a pool of ribonucleotide triphosphates,a buffer system that may include DTT and magnesium ions, and anappropriate RNA polymerase (e.g., T3, T7, mutated T7 or SP6 RNApolymerase), DNAse I, pyrophosphatase, and/or RNAse inhibitor. The exactconditions will vary according to the specific application.

In some embodiments, for the preparation of mRNA according to theinvention, a DNA template is transcribed in vitro. A suitable DNAtemplate typically has a promoter, for example a T3, T7, mutated T7 orSP6 promoter, for in vitro transcription, followed by desired nucleotidesequence for desired mRNA and a termination signal.

Desired mRNA sequence(s) according to the invention may be determinedand incorporated into a DNA template using standard methods. Forexample, starting from a desired amino acid sequence (e.g., an enzymesequence), a virtual reverse translation is carried out based on thedegenerated genetic code. Optimization algorithms may then be used forselection of suitable codons. Typically, the G/C content can beoptimized to achieve the highest possible G/C content on one hand,taking into the best possible account the frequency of the tRNAsaccording to codon usage on the other hand. The optimized RNA sequencecan be established and displayed, for example, with the aid of anappropriate display device and compared with the original (wild-type)sequence. A secondary structure can also be analyzed to calculatestabilizing and destabilizing properties or, respectively, regions ofthe RNA.

Modified Nucleic Acids

Modified nucleic acids according to the present invention may be includemodifications and be prepared according to any known modifications andmethods. For example, in some embodiments, mRNA according to the presentinvention may be synthesized as unmodified RNA or as modified RNA inaccordance with known modifications and methods. Typically, RNAs aremodified to enhance stability. Modifications of RNA can include, forexample, modifications of the nucleotides of the RNA. A modified RNAsuch as modified mRNA (mmRNA) according to the invention can thusinclude, for example, backbone modifications, sugar modifications orbase modifications. In some embodiments, mRNAs may be synthesized fromnaturally occurring nucleotides and/or nucleotide analogues (modifiednucleotides) including, but not limited to, purines (adenine (A),guanine (G)) or pyrimidines (thymine (T), cytosine (C), uracil (U)), andas modified nucleotides analogues or derivatives of purines andpyrimidines, such as e.g. 1-methyl-adenine, 2-methyl-adenine,2-methylthio-N-6-isopentenyl-adenine, N6-methyl-adenine,N6-isopentenyl-adenine, 2-thio-cytosine, 3-methyl-cytosine,4-acetyl-cytosine, 5-methyl-cytosine, 2,6-diaminopurine,1-methyl-guanine, 2-methyl-guanine, 2,2-dimethyl-guanine,7-methyl-guanine, inosine, 1-methyl-inosine, pseudouracil (5-uracil),dihydro-uracil, 2-thio-uracil, 4-thio-uracil,5-carboxymethylaminomethyl-2-thio-uracil,5-(carboxyhydroxymethyl)-uracil, 5-fluoro-uracil, 5-bromo-uracil,5-carboxymethylaminomethyl-uracil, 5-methyl-2-thio-uracil,5-methyl-uracil, N-uracil-5-oxyacetic acid methyl ester,5-methylaminomethyl-uracil, 5-methoxyaminomethyl-2-thio-uracil,5′-methoxycarbonylmethyl-uracil, 5-methoxy-uracil, uracil-5-oxyaceticacid methyl ester, uracil-5-oxyacetic acid (v), 1-methyl-pseudouracil,queosine, .beta.-D-mannosyl-queosine, wybutoxosine, andphosphoramidates, phosphorothioates, peptide nucleotides,methylphosphonates, 7-deazaguanosine, 5-methylcytosine and inosine. Thepreparation of such analogues is known to a person skilled in the arte.g., from the U.S. Pat. Nos. 4,373,071, 4,401,796, 4,415,732,4,458,066, 4,500,707, 4,668,777, 4,973,679, 5,047,524, 5,132,418,5,153,319, 5,262,530 and 5,700,642, the disclosures of which areincorporated by reference in their entirety.

In some embodiments, modified RNAs such as mmRNAs may contain RNAbackbone modifications. Typically, a backbone modification is amodification in which the phosphates of the backbone of the nucleotidescontained in the RNA are modified chemically. Exemplary backbonemodifications typically include, but are not limited to, modificationsfrom the group consisting of methylphosphonates, methylphosphoramidates,phosphoramidates, phosphorothioates (e.g. cytidine5′-O-(1-thiophosphate)), boranophosphates, positively chargedguanidinium groups etc., which means by replacing the phosphodiesterlinkage by other anionic, cationic or neutral groups.

In some embodiments, modified RNAs such as mmRNAs may contain sugarmodifications. A typical sugar modification is a chemical modificationof the sugar of the nucleotides it contains including, but not limitedto, sugar modifications chosen from the group consisting of4′-thio-ribonucleotide (see, e.g., US Patent Application Publication No.US 2016/0031928, incorporated by reference herein),2′-deoxy-2′-fluoro-oligoribonucleotide (2′-fluoro-2′-deoxycytidine5′-triphosphate, 2′-fluoro-2′-deoxyuridine 5′-triphosphate),2′-deoxy-2′-deamine-oligoribonucleotide (2′-amino-2′-deoxycytidine5′-triphosphate, 2′-amino-2′-deoxyuridine 5′-triphosphate),2′-O-alkyloligoribonucleotide, 2′-deoxy-2′-C-alkyloligoribonucleotide(2′-O-methylcytidine 5′-triphosphate, 2′-methyluridine 5′-triphosphate),2′-C-alkyloligoribonucleotide, and isomers thereof (2′-aracytidine5′-triphosphate, 2′-arauridine 5′-triphosphate), or azidotriphosphates(2′-azido-2′-deoxycytidine 5′-triphosphate, 2′-azido-2′-deoxyuridine5′-triphosphate).

In some embodiments, modified RNAs such as mmRNAs may containmodifications of the bases of the nucleotides (base modifications). Amodified nucleotide which contains a base modification is also called abase-modified nucleotide. Examples of such base-modified nucleotidesinclude, but are not limited to, 2-amino-6-chloropurine riboside5′-triphosphate, 2-aminoadenosine 5′-triphosphate, 2-thiocytidine5′-triphosphate, 2-thiouridine 5′-triphosphate, 4-thiouridine5′-triphosphate, 5-aminoallylcytidine 5′-triphosphate,5-aminoallyluridine 5′-triphosphate, 5-bromocytidine 5′-triphosphate,5-bromouridine 5′-triphosphate, 5-iodocytidine 5′-triphosphate,5-iodouridine 5′-triphosphate, 5-methylcytidine 5′-triphosphate,5-methyluridine 5′-triphosphate, 6-azacytidine 5′-triphosphate,6-azauridine 5′-triphosphate, 6-chloropurine riboside 5′-triphosphate,7-deazaadenosine 5′-triphosphate, 7-deazaguanosine 5′-triphosphate,8-azaadenosine 5′-triphosphate, 8-azidoadenosine 5′-triphosphate,benzimidazole riboside 5′-triphosphate, N1-methyladenosine5′-triphosphate, N1-methylguanosine 5′-triphosphate, N6-methyladenosine5′-triphosphate, 06-methylguanosine 5′-triphosphate, pseudouridine5′-triphosphate, puromycin 5′-triphosphate or xanthosine5′-triphosphate.

Typically, mRNA synthesis includes the addition of a “cap” on theN-terminal (5′) end, and a “tail” on the C-terminal (3′) end. Thepresence of the cap is important in providing resistance to nucleasesfound in most eukaryotic cells. The presence of a “tail” serves toprotect the mRNA from exonuclease degradation.

Thus, in some embodiments, mRNAs include a 5′ cap structure. A 5′ cap istypically added as follows: first, an RNA terminal phosphatase removesone of the terminal phosphate groups from the 5′ nucleotide, leaving twoterminal phosphates; guanosine triphosphate (GTP) is then added to theterminal phosphates via a guanylyl transferase, producing a 5′5′5triphosphate linkage; and the 7-nitrogen of guanine is then methylatedby a methyltransferase. Examples of cap structures include, but are notlimited to, m7G(5′)ppp (5′(A,G(5′)ppp(5′)A and G(5′)ppp(5′)G.

In some embodiments, mRNAs include a 3′ poly(A) tail structure. A poly-Atail on the 3′ terminus of mRNA typically includes about 10 to 300adenosine nucleotides (SEQ ID NO: 4) (e.g., about 10 to 200 adenosinenucleotides, about 10 to 150 adenosine nucleotides, about 10 to 100adenosine nucleotides, about 20 to 70 adenosine nucleotides, or about 20to 60 adenosine nucleotides). In some embodiments, mRNAs include a 3′poly(C) tail structure. A suitable poly-C tail on the 3′ terminus ofmRNA typically include about 10 to 200 cytosine nucleotides (SEQ ID NO:5) (e.g., about 10 to 150 cytosine nucleotides, about 10 to 100 cytosinenucleotides, about 20 to 70 cytosine nucleotides, about 20 to 60cytosine nucleotides, or about 10 to 40 cytosine nucleotides). Thepoly-C tail may be added to the poly-A tail or may substitute the poly-Atail.

In some embodiments, mRNAs include a 5′ and/or 3′ untranslated region.In some embodiments, a 5′ untranslated region includes one or moreelements that affect an mRNA's stability or translation, for example, aniron responsive element. In some embodiments, a 5′ untranslated regionmay be between about 50 and 500 nucleotides in length.

In some embodiments, a 3′ untranslated region includes one or more of apolyadenylation signal, a binding site for proteins that affect anmRNA's stability of location in a cell, or one or more binding sites formiRNAs. In some embodiments, a 3′ untranslated region may be between 50and 500 nucleotides in length or longer.

Cap Structure

In some embodiments, mRNAs include a 5′ cap structure. A 5′ cap istypically added as follows: first, an RNA terminal phosphatase removesone of the terminal phosphate groups from the 5′ nucleotide, leaving twoterminal phosphates; guanosine triphosphate (GTP) is then added to theterminal phosphates via a guanylyl transferase, producing a 5′5′5triphosphate linkage; and the 7-nitrogen of guanine is then methylatedby a methyltransferase. Examples of cap structures include, but are notlimited to, m7G(5′)ppp (5′(A,G(5′)ppp(5′)A and G(5′)ppp(5′)G.

Naturally occurring cap structures comprise a 7-methyl guanosine that islinked via a triphosphate bridge to the 5′-end of the first transcribednucleotide, resulting in a dinucleotide cap of m⁷G(5′)ppp(5′)N, where Nis any nucleoside. In vivo, the cap is added enzymatically. The cap isadded in the nucleus and is catalyzed by the enzyme guanylyltransferase. The addition of the cap to the 5′ terminal end of RNAoccurs immediately after initiation of transcription. The terminalnucleoside is typically a guanosine, and is in the reverse orientationto all the other nucleotides, i.e., G(5′)ppp(5′)GpNpNp.

A common cap for mRNA produced by in vitro transcription ism⁷G(5′)ppp(5′)G, which has been used as the dinucleotide cap intranscription with T7 or SP6 RNA polymerase in vitro to obtain RNAshaving a cap structure in their 5′-termini. The prevailing method forthe in vitro synthesis of capped mRNA employs a pre-formed dinucleotideof the form m⁷G(5′)ppp(5′)G (“m⁷GpppG”) as an initiator oftranscription.

To date, a usual form of a synthetic dinucleotide cap used in in vitrotranslation experiments is the Anti-Reverse Cap Analog (“ARCA”) ormodified ARCA, which is generally a modified cap analog in which the 2′or 3′ OH group is replaced with —OCH₃.

Additional cap analogs include, but are not limited to, a chemicalstructures selected from the group consisting of m⁷GpppG, m⁷GpppA,m⁷GpppC; unmethylated cap analogs (e.g., GpppG); dimethylated cap analog(e.g., m²′7GpppG), trimethylated cap analog (e.g., m^(2,2,7)GpppG),dimethylated symmetrical cap analogs (e.g., m⁷Gpppm⁷G), or anti reversecap analogs (e.g., ARCA; m^(7,2′Ome)GpppG, m^(72′d)GpppG,m^(7,3′Ome)GpppG, m^(7,3,d)GpppG and their tetraphosphate derivatives)(see, e.g., Jemielity, J. et al., “Novel ‘anti-reverse’ cap analogs withsuperior translational properties”, RNA, 9: 1108-1122 (2003)).

In some embodiments, a suitable cap is a 7-methyl guanylate (“m⁷G”)linked via a triphosphate bridge to the 5′-end of the first transcribednucleotide, resulting in m⁷G(5′)ppp(5′)N, where N is any nucleoside. Apreferred embodiment of a m⁷G cap utilized in embodiments of theinvention is m⁷G(5′)ppp(5′)G.

In some embodiments, the cap is a Cap0 structure. Cap0 structures lack a2′-O-methyl residue of the ribose attached to bases 1 and 2. In someembodiments, the cap is a Cap1 structure. Cap1 structures have a2′-O-methyl residue at base 2. In some embodiments, the cap is a Cap2structure. Cap2 structures have a 2′-O-methyl residue attached to bothbases 2 and 3.

A variety of m⁷G cap analogs are known in the art, many of which arecommercially available. These include the m⁷GpppG described above, aswell as the ARCA 3′-OCH₃ and 2′-OCH₃ cap analogs (Jemielity, J. et al.,RNA, 9: 1108-1122 (2003)). Additional cap analogs for use in embodimentsof the invention include N7-benzylated dinucleoside tetraphosphateanalogs (described in Grudzien, E. et al., RNA, 10: 1479-1487 (2004)),phosphorothioate cap analogs (described in Grudzien-Nogalska, E., etal., RNA, 13: 1745-1755 (2007)), and cap analogs (including biotinylatedcap analogs) described in U.S. Pat. Nos. 8,093,367 and 8,304,529,incorporated by reference herein.

Tail Structure

Typically, the presence of a “tail” serves to protect the mRNA fromexonuclease degradation. The poly A tail is thought to stabilize naturalmessengers and synthetic sense RNA. Therefore, in certain embodiments along poly A tail can be added to an mRNA molecule thus rendering the RNAmore stable. Poly A tails can be added using a variety of art-recognizedtechniques. For example, long poly A tails can be added to synthetic orin vitro transcribed RNA using poly A polymerase (Yokoe, et al. NatureBiotechnology. 1996; 14: 1252-1256). A transcription vector can alsoencode long poly A tails. In addition, poly A tails can be added bytranscription directly from PCR products. Poly A may also be ligated tothe 3′ end of a sense RNA with RNA ligase (see, e.g., Molecular CloningA Laboratory Manual, 2nd Ed., ed. by Sambrook, Fritsch and Maniatis(Cold Spring Harbor Laboratory Press: 1991 edition)).

In some embodiments, mRNAs include a 3′ poly(A) tail structure.Typically, the length of the poly A tail can be at least about 10, 50,100, 200, 300, 400 at least 500 nucleotides. In some embodiments, apoly-A tail on the 3′ terminus of mRNA typically includes about 10 to300 adenosine nucleotides (e.g., about 10 to 200 adenosine nucleotides,about 10 to 150 adenosine nucleotides, about 10 to 100 adenosinenucleotides, about 20 to 70 adenosine nucleotides, or about 20 to 60adenosine nucleotides). In some embodiments, mRNAs include a 3′ poly(C)tail structure. A suitable poly-C tail on the 3′ terminus of mRNAtypically include about 10 to 200 cytosine nucleotides (e.g., about 10to 150 cytosine nucleotides, about 10 to 100 cytosine nucleotides, about20 to 70 cytosine nucleotides, about 20 to 60 cytosine nucleotides, orabout 10 to 40 cytosine nucleotides). The poly-C tail may be added tothe poly-A tail or may substitute the poly-A tail.

In some embodiments, the length of the poly A or poly C tail is adjustedto control the stability of a modified sense mRNA molecule of theinvention and, thus, the transcription of protein. For example, sincethe length of the poly A tail can influence the half-life of a sensemRNA molecule, the length of the poly A tail can be adjusted to modifythe level of resistance of the mRNA to nucleases and thereby control thetime course of polynucleotide expression and/or polypeptide productionin a target cell.

5′ and 3′ Untranslated Region

In some embodiments, mRNAs include a 5′ and/or 3′ untranslated region.In some embodiments, a 5′ untranslated region includes one or moreelements that affect an mRNA's stability or translation, for example, aniron responsive element. In some embodiments, a 5′ untranslated regionmay be between about 50 and 500 nucleotides in length.

In some embodiments, a 3′ untranslated region includes one or more of apolyadenylation signal, a binding site for proteins that affect anmRNA's stability of location in a cell, or one or more binding sites formiRNAs. In some embodiments, a 3′ untranslated region may be between 50and 500 nucleotides in length or longer.

Exemplary 3′ and/or 5′ UTR sequences can be derived from mRNA moleculeswhich are stable (e.g., globin, actin, GAPDH, tubulin, histone, orcitric acid cycle enzymes) to increase the stability of the sense mRNAmolecule. For example, a 5′ UTR sequence may include a partial sequenceof a CMV immediate-early 1 (IE1) gene, or a fragment thereof to improvethe nuclease resistance and/or improve the half-life of thepolynucleotide. Also contemplated is the inclusion of a sequenceencoding human growth hormone (hGH), or a fragment thereof to the 3′ endor untranslated region of the polynucleotide (e.g., mRNA) to furtherstabilize the polynucleotide. Generally, these modifications improve thestability and/or pharmacokinetic properties (e.g., half-life) of thepolynucleotide relative to their unmodified counterparts, and include,for example modifications made to improve such polynucleotides'resistance to in vivo nuclease digestion.

Pharmaceutical Formulations of Polymers and Nucleic Acids

Among other things, the present invention provides a pharmaceuticalformulation comprising a provided polymer and one or more nucleic acids.As described below, such a polymer-based formulation for deliveringnucleic acids can provide one or more advantages in delivering nucleicacids, such as mRNA, for providing a therapeutic benefit, such asproducing encoded protein (where the nucleic acid is mRNA), overexisting polymers.

In one aspect, the invention features a pharmaceutical compositioncomprising a polymer as described herein and one or morepolynucleotides.

In embodiments, a polynucleotide comprises RNA (e.g., mRNA, siRNA,snoRNA, microRNA, gRNA, crRNA and combinations thereof).

In embodiments, an RNA is mRNA.

I

mRNA encodes a peptide or polypeptide for use in the delivery to ortreatment of the lung of a subject or a lung cell. In embodiments, anmRNA encodes cystic fibrosis transmembrane conductance regulator (CFTR)protein.

mRNA encodes a peptide or polypeptide for use in the delivery to ortreatment of the liver of a subject or a liver cell. In embodiments, anmRNA encodes ornithine transcarbamylase (OTC) protein.

In embodiments, an mRNA encodes a peptide or polypeptide for use invaccine. In embodiments, an mRNA encodes an antigen.

In general, the polymer and nucleic acids such as mRNA are first mixedin a solution, e.g., an aqueous solution. Typically, the polymer andnucleic acids such as mRNA form a complex when mixed. In someembodiments, the polymer and nucleic acids are complexed in a form ofnanoparticles.

Various sized nanoparticles may be formed according to the presentinvention. In various embodiments, a nanoparticle is characterized withan average diameter based on volume diameter using dynamic lightscattering. In some embodiments, nanoparticles have an average diameterbetween about 50 nm and about 250 nm. In some embodiments, nanoparticleshave an average diameter between about 50 nm and about 200 nm. In someembodiments, nanoparticles have an average diameter between about 75 nmand about 225 nm. In some embodiments, nanoparticles have an averagediameter between about 100 nm and about 200 nm. In some embodiments,nanoparticles have an average diameter between about 125 nm and about175 nm. In some embodiments, nanoparticles have an average diameterbetween about 140 nm and about 160 nm. In some embodiments,nanoparticles have an average diameter between about 50 nm and about 150nm. In some embodiments, nanoparticles have an average diameter betweenabout 75 nm and about 125 nm. In some embodiments, nanoparticles have anaverage diameter between about 50 nm and about 250 nm. In someembodiments, nanoparticles have an average diameter between about 90 nmand about 110 nm. In some embodiments, nanoparticles have an averagediameter between about 150 nm and about 250 nm. In some embodiments,nanoparticles have an average diameter between about 175 nm and about225 nm. In some embodiments, nanoparticles have an average diameterbetween about 190 nm and about 210 nm.

Nanoparticles may have a range of sizes in a mixture. Typically, thenanoparticles have a polydispersity index (PDI) of less than about 0.5(e.g., less than about 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, or 0.1).In some embodiment, the nanoparticles have a PDI between about 0.1 andabout 0.4. In some embodiments nanoparticles have a PDI between about0.1 and about 0.4. In some embodiments nanoparticles have a PDI betweenabout 0.1 and about 0.2. In some embodiments nanoparticles have a PDIbetween about 0.2 and about 0.3. In some embodiments, nanoparticles havea PDI between about 0.3 and about 0.4.

Nanoparticles may have a range of surface charges as measured throughzeta potential measurements. In some embodiments, nanoparticles have azeta potential between 0 and about 50 mV. In some embodimentsnanoparticles have a zeta potential between about 5 and about 45 mV. Insome embodiments nanoparticles have a zeta potential between about 10and about 40 mV. In some embodiments nanoparticles have a zeta potentialbetween about 10 and about 30 mV. In some embodiments nanoparticles havea zeta potential between about 20 and about 30 mV.

Pharmaceutical Formulations and Therapeutic Uses

Pharmaceutical formulations containing provided polymer and nucleicacids provided by the present invention may be used for varioustherapeutic purposes. Provided polymer-based formulations for deliveringnucleic acids can provide one or more advantages in delivering nucleicacids, such as mRNA, for providing a therapeutic benefit, such asproducing encoded protein (where the nucleic acid is mRNA), overexisting polymers.

Provided polymers are biodegradable. Biodegradable polymers can providea higher level of tolerability than other polymeric and lipidic deliveryvehicles.

Provided polymers are ionizable. The ionizability can be engendered byan amino functionality in the polymer backbone (e.g., R is N) and/or aprotonatable group tethered from the backbone. The protonatable groupwill have at least one 1° amino, 2° amino, 3° amino or imidazolylfunctionality. Such ionizable groups can provide a buffering effect andact as a “proton sponge” allowing for enhancement of endosomal release.

Provided polymers incorporate an S-acycl-2-thioethyl (“SATE”) protectinggroup on the phosphate groups within the backbone. Such protectionremoves the negative charge from the phosphate groups, allowing forfacile complexation of the ionizable positively charged polymer withnucleic acids. Upon cellular entry, the SATE protecting groups arebiolabile and can be cleaved enzymatically by carboxylesterase. Suchcleavage and results in a negatively charged phosphate moiety across thebackbone of polymers. This, in effect, neutralizes the polymer chargeand thus removes the electrostatic ability of the polymer to bindnucleic acids, e.g., mRNA. This can result in efficient release of thepayload nucleic acid.

To facilitate delivery of nucleic acids in vivo, polymer/nucleic acidscan be formulated in combination with one or more additionalpharmaceutical carriers, targeting ligands or stabilizing reagents.Techniques for formulation and administration of drugs may be found in“Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, Pa.,latest edition.

Suitable routes of administration include, for example, oral, rectal,vaginal, transmucosal, pulmonary including intratracheal or inhaled, orintestinal administration; parenteral delivery, including intradermal,transdermal (topical), intramuscular, subcutaneous, intramedullaryinjections, as well as intrathecal, direct intraventricular,intravenous, intraperitoneal, or intranasal. In particular embodiments,the intramuscular administration is to a muscle selected from the groupconsisting of skeletal muscle, smooth muscle and cardiac muscle. In someembodiments the administration results in delivery of the nucleic acidsto a muscle cell. In some embodiments the administration results indelivery of the nucleic acids to a hepatocyte (i.e., liver cell).

Alternatively or additionally, pharmaceutical formulations of theinvention may be administered in a local rather than systemic manner,for example, via injection of the pharmaceutical formulation directlyinto a targeted tissue, preferably in a sustained release formulation.Local delivery can be affected in various ways, depending on the tissueto be targeted. For example, aerosols containing compositions of thepresent invention can be inhaled (for nasal, tracheal, or bronchialdelivery); compositions of the present invention can be injected intothe site of injury, disease manifestation, or pain, for example;compositions can be provided in lozenges for oral, tracheal, oresophageal application; can be supplied in liquid, tablet or capsuleform for administration to the stomach or intestines, can be supplied insuppository form for rectal or vaginal application; or can even bedelivered to the eye by use of creams, drops, or even injection.

The present invention provides methods for producing a compositionenriched with full-length mRNA molecules which are greater than 500nucleotides in length and encoding for a peptide or polypeptide ofinterest. The present invention also provides methods for producing atherapeutic composition enriched with full-length mRNA moleculesencoding a peptide or polypeptide of interest for use in the delivery toor treatment of a subject, e.g., a human subject or a cell of a humansubject or a cell that is treated and delivered to a human subject.

Accordingly, in certain embodiments the present invention provides amethod for producing a therapeutic composition enriched with full-lengthmRNA that encodes a peptide or polypeptide for use in the delivery to ortreatment of the lung of a subject or a lung cell. In certainembodiments the present invention provides a method for producing atherapeutic composition enriched with full-length mRNA that encodes forcystic fibrosis transmembrane conductance regulator (CFTR) protein. Incertain embodiments the present invention provides a method forproducing a therapeutic composition enriched with full-length mRNA thatencodes for ATP-binding cassette sub-family A member 3 protein. Incertain embodiments the present invention provides a method forproducing a therapeutic composition enriched with full-length mRNA thatencodes for dynein axonemal intermediate chain 1 protein. In certainembodiments the present invention provides a method for producing atherapeutic composition enriched with full-length mRNA that encodes fordynein axonemal heavy chain 5 (DNAH5) protein. In certain embodimentsthe present invention provides a method for producing a therapeuticcomposition enriched with full-length mRNA that encodes foralpha-1-antitrypsin protein. In certain embodiments the presentinvention provides a method for producing a therapeutic compositionenriched with full-length mRNA that encodes for forkhead box P3 (FOXP3)protein. In certain embodiments the present invention provides a methodfor producing a therapeutic composition enriched with full-length mRNAthat encodes one or more surfactant protein, e.g., one or more ofsurfactant A protein, surfactant B protein, surfactant C protein, andsurfactant D protein.

In certain embodiments the present invention provides a method forproducing a therapeutic composition enriched with full-length mRNA thatencodes a peptide or polypeptide for use in the delivery to or treatmentof the liver of a subject or a liver cell. Such peptides andpolypeptides can include those associated with a urea cycle disorder,associated with a lysosomal storage disorder, with a glycogen storagedisorder, associated with an amino acid metabolism disorder, associatedwith a lipid metabolism or fibrotic disorder, associated withmethylmalonic acidemia, or associated with any other metabolic disorderfor which delivery to or treatment of the liver or a liver cell withenriched full-length mRNA provides therapeutic benefit.

In certain embodiments the present invention provides a method forproducing a therapeutic composition enriched with full-length mRNA thatencodes for a protein associated with a urea cycle disorder. In certainembodiments the present invention provides a method for producing atherapeutic composition enriched with full-length mRNA that encodes forornithine transcarbamylase (OTC) protein. In certain embodiments thepresent invention provides a method for producing a therapeuticcomposition enriched with full-length mRNA that encodes forarginosuccinate synthetase 1 protein. In certain embodiments the presentinvention provides a method for producing a therapeutic compositionenriched with full-length mRNA that encodes for carbamoyl phosphatesynthetase I protein. In certain embodiments the present inventionprovides a method for producing a therapeutic composition enriched withfull-length mRNA that encodes for arginosuccinate lyase protein. Incertain embodiments the present invention provides a method forproducing a therapeutic composition enriched with full-length mRNA thatencodes for arginase protein.

In certain embodiments the present invention provides a method forproducing a therapeutic composition enriched with full-length mRNA thatencodes for a protein associated with a lysosomal storage disorder. Incertain embodiments the present invention provides a method forproducing a therapeutic composition enriched with full-length mRNA thatencodes for alpha galactosidase protein. In certain embodiments thepresent invention provides a method for producing a therapeuticcomposition enriched with full-length mRNA that encodes forglucocerebrosidase protein. In certain embodiments the present inventionprovides a method for producing a therapeutic composition enriched withfull-length mRNA that encodes for iduronate-2-sulfatase protein. Incertain embodiments the present invention provides a method forproducing a therapeutic composition enriched with full-length mRNA thatencodes for iduronidase protein. In certain embodiments the presentinvention provides a method for producing a therapeutic compositionenriched with full-length mRNA that encodes forN-acetyl-alpha-D-glucosaminidase protein. In certain embodiments thepresent invention provides a method for producing a therapeuticcomposition enriched with full-length mRNA that encodes for heparanN-sulfatase protein. In certain embodiments the present inventionprovides a method for producing a therapeutic composition enriched withfull-length mRNA that encodes for galactosamine-6 sulfatase protein. Incertain embodiments the present invention provides a method forproducing a therapeutic composition enriched with full-length mRNA thatencodes for beta-galactosidase protein. In certain embodiments thepresent invention provides a method for producing a therapeuticcomposition enriched with full-length mRNA that encodes for lysosomallipase protein. In certain embodiments the present invention provides amethod for producing a therapeutic composition enriched with full-lengthmRNA that encodes for arylsulfatase B(N-acetylgalactosamine-4-sulfatase) protein. In certain embodiments thepresent invention provides a method for producing a therapeuticcomposition enriched with full-length mRNA that encodes fortranscription factor EB (TFEB).

In certain embodiments the present invention provides a method forproducing a therapeutic composition enriched with full-length mRNA thatencodes for a protein associated with a glycogen storage disorder. Incertain embodiments the present invention provides a method forproducing a therapeutic composition enriched with full-length mRNA thatencodes for acid alpha-glucosidase protein. In certain embodiments thepresent invention provides a method for producing a therapeuticcomposition enriched with full-length mRNA that encodes forglucose-6-phosphatase (G6PC) protein. In certain embodiments the presentinvention provides a method for producing a therapeutic compositionenriched with full-length mRNA that encodes for liver glycogenphosphorylase protein. In certain embodiments the present inventionprovides a method for producing a therapeutic composition enriched withfull-length mRNA that encodes for muscle phosphoglycerate mutaseprotein. In certain embodiments the present invention provides a methodfor producing a therapeutic composition enriched with full-length mRNAthat encodes for glycogen debranching enzyme.

In certain embodiments the present invention provides a method forproducing a therapeutic composition enriched with full-length mRNA thatencodes for a protein associated with amino acid metabolism. In certainembodiments the present invention provides a method for producing atherapeutic composition enriched with full-length mRNA that encodes forphenylalanine hydroxylase enzyme. In certain embodiments the presentinvention provides a method for producing a therapeutic compositionenriched with full-length mRNA that encodes for glutaryl-CoAdehydrogenase enzyme. In certain embodiments the present inventionprovides a method for producing a therapeutic composition enriched withfull-length mRNA that encodes for propionyl-CoA caboxylase enzyme. Incertain embodiments the present invention provides a method forproducing a therapeutic composition enriched with full-length mRNA thatencodes for oxalase alanine-glyoxylate aminotransferase enzyme.

In certain embodiments the present invention provides a method forproducing a therapeutic composition enriched with full-length mRNA thatencodes for a protein associated with a lipid metabolism or fibroticdisorder. In certain embodiments the present invention provides a methodfor producing a therapeutic composition enriched with full-length mRNAthat encodes for a mTOR inhibitor. In certain embodiments the presentinvention provides a method for producing a therapeutic compositionenriched with full-length mRNA that encodes for ATPase phospholipidtransporting 8B1 (ATP8B1) protein. In certain embodiments the presentinvention provides a method for producing a therapeutic compositionenriched with full-length mRNA that encodes for one or more NF-kappa Binhibitors, such as one or more of I-kappa B alpha, interferon-relateddevelopment regulator 1 (IFRD1), and Sirtuin 1 (SIRT1). In certainembodiments the present invention provides a method for producing atherapeutic composition enriched with full-length mRNA that encodes forPPAR-gamma protein or an active variant.

In certain embodiments the present invention provides a method forproducing a therapeutic composition enriched with full-length mRNA thatencodes for a protein associated with methylmalonic acidemia. Forexample, in certain embodiments the present invention provides a methodfor producing a therapeutic composition enriched with full-length mRNAthat encodes for methylmalonyl CoA mutase protein. In certainembodiments the present invention provides a method for producing atherapeutic composition enriched with full-length mRNA that encodes formethylmalonyl CoA epimerase protein.

In certain embodiments the present invention provides a method forproducing a therapeutic composition enriched with full-length mRNA forwhich delivery to or treatment of the liver can provide therapeuticbenefit. In certain embodiments the present invention provides a methodfor producing a therapeutic composition enriched with full-length mRNAthat encodes for ATP7B protein, also known as Wilson disease protein. Incertain embodiments the present invention provides a method forproducing a therapeutic composition enriched with full-length mRNA thatencodes for porphobilinogen deaminase enzyme. In certain embodiments thepresent invention provides a method for producing a therapeuticcomposition enriched with full-length mRNA that encodes for one orclotting enzymes, such as Factor VIII, Factor IX, Factor VII, and FactorX. In certain embodiments the present invention provides a method forproducing a therapeutic composition enriched with full-length mRNA thatencodes for human hemochromatosis (HFE) protein.

In certain embodiments the present invention provides a method forproducing a therapeutic composition enriched with full-length mRNA thatencodes a peptide or polypeptide for use in the delivery to or treatmentof the cardiovasculature of a subject or a cardiovascular cell. Incertain embodiments the present invention provides a method forproducing a therapeutic composition enriched with full-length mRNA thatencodes for vascular endothelial growth factor A protein. In certainembodiments the present invention provides a method for producing atherapeutic composition enriched with full-length mRNA that encodes forrelaxin protein. In certain embodiments the present invention provides amethod for producing a therapeutic composition enriched with full-lengthmRNA that encodes for bone morphogenetic protein-9 protein. In certainembodiments the present invention provides a method for producing atherapeutic composition enriched with full-length mRNA that encodes forbone morphogenetic protein-2 receptor protein.

In certain embodiments the present invention provides a method forproducing a therapeutic composition enriched with full-length mRNA thatencodes a peptide or polypeptide for use in the delivery to or treatmentof the muscle of a subject or a muscle cell. In certain embodiments thepresent invention provides a method for producing a therapeuticcomposition enriched with full-length mRNA that encodes for dystrophinprotein. In certain embodiments the present invention provides a methodfor producing a therapeutic composition enriched with full-length mRNAthat encodes for frataxin protein. In certain embodiments the presentinvention provides a method for producing a therapeutic compositionenriched with full-length mRNA that encodes a peptide or polypeptide foruse in the delivery to or treatment of the cardiac muscle of a subjector a cardiac muscle cell. In certain embodiments the present inventionprovides a method for producing a therapeutic composition enriched withfull-length mRNA that encodes for a protein that modulates one or bothof a potassium channel and a sodium channel in muscle tissue or in amuscle cell. In certain embodiments the present invention provides amethod for producing a therapeutic composition enriched with full-lengthmRNA that encodes for a protein that modulates a Kv7.1 channel in muscletissue or in a muscle cell. In certain embodiments the present inventionprovides a method for producing a therapeutic composition enriched withfull-length mRNA that encodes for a protein that modulates a Nav1.5channel in muscle tissue or in a muscle cell.

In certain embodiments the present invention provides a method forproducing a therapeutic composition enriched with full-length mRNA thatencodes a peptide or polypeptide for use in the delivery to or treatmentof the nervous system of a subject or a nervous system cell. Forexample, in certain embodiments the present invention provides a methodfor producing a therapeutic composition enriched with full-length mRNAthat encodes for survival motor neuron 1 protein. For example, incertain embodiments the present invention provides a method forproducing a therapeutic composition enriched with full-length mRNA thatencodes for survival motor neuron 2 protein. In certain embodiments thepresent invention provides a method for producing a therapeuticcomposition enriched with full-length mRNA that encodes for frataxinprotein. In certain embodiments the present invention provides a methodfor producing a therapeutic composition enriched with full-length mRNAthat encodes for ATP binding cassette subfamily D member 1 (ABCD1)protein. In certain embodiments the present invention provides a methodfor producing a therapeutic composition enriched with full-length mRNAthat encodes for CLN3 protein.

In certain embodiments the present invention provides a method forproducing a therapeutic composition enriched with full-length mRNA thatencodes a peptide or polypeptide for use in the delivery to or treatmentof the blood or bone marrow of a subject or a blood or bone marrow cell.In certain embodiments the present invention provides a method forproducing a therapeutic composition enriched with full-length mRNA thatencodes for beta globin protein. In certain embodiments the presentinvention provides a method for producing a therapeutic compositionenriched with full-length mRNA that encodes for Bruton's tyrosine kinaseprotein. In certain embodiments the present invention provides a methodfor producing a therapeutic composition enriched with full-length mRNAthat encodes for one or clotting enzymes, such as Factor VIII, FactorIX, Factor VII, and Factor X.

In certain embodiments the present invention provides a method forproducing a therapeutic composition enriched with full-length mRNA thatencodes a peptide or polypeptide for use in the delivery to or treatmentof the kidney of a subject or a kidney cell. In certain embodiments thepresent invention provides a method for producing a therapeuticcomposition enriched with full-length mRNA that encodes for collagentype IV alpha 5 chain (COL4A5) protein.

In certain embodiments the present invention provides a method forproducing a therapeutic composition enriched with full-length mRNA thatencodes a peptide or polypeptide for use in the delivery to or treatmentof the eye of a subject or an eye cell. In certain embodiments thepresent invention provides a method for producing a therapeuticcomposition enriched with full-length mRNA that encodes for ATP-bindingcassette sub-family A member 4 (ABCA4) protein. In certain embodimentsthe present invention provides a method for producing a therapeuticcomposition enriched with full-length mRNA that encodes forretinoschisin protein. In certain embodiments the present inventionprovides a method for producing a therapeutic composition enriched withfull-length mRNA that encodes for retinal pigment epithelium-specific 65kDa (RPE65) protein. In certain embodiments the present inventionprovides a method for producing a therapeutic composition enriched withfull-length mRNA that encodes for centrosomal protein of 290 kDa(CEP290).

In certain embodiments the present invention provides a method forproducing a therapeutic composition enriched with full-length mRNA thatencodes a peptide or polypeptide for use in the delivery of or treatmentwith a vaccine for a subject or a cell of a subject. For example, incertain embodiments the present invention provides a method forproducing a therapeutic composition enriched with full-length mRNA thatencodes for an antigen from an infectious agent, such as a virus. Incertain embodiments the present invention provides a method forproducing a therapeutic composition enriched with full-length mRNA thatencodes for an antigen from influenza virus. In certain embodiments thepresent invention provides a method for producing a therapeuticcomposition enriched with full-length mRNA that encodes for an antigenfrom respiratory syncytial virus. In certain embodiments the presentinvention provides a method for producing a therapeutic compositionenriched with full-length mRNA that encodes for an antigen from rabiesvirus. In certain embodiments the present invention provides a methodfor producing a therapeutic composition enriched with full-length mRNAthat encodes for an antigen from cytomegalovirus. In certain embodimentsthe present invention provides a method for producing a therapeuticcomposition enriched with full-length mRNA that encodes for an antigenfrom rotavirus. In certain embodiments the present invention provides amethod for producing a therapeutic composition enriched with full-lengthmRNA that encodes for an antigen from a hepatitis virus, such ashepatitis A virus, hepatitis B virus, or hepatis C virus. In certainembodiments the present invention provides a method for producing atherapeutic composition enriched with full-length mRNA that encodes foran antigen from human papillomavirus. In certain embodiments the presentinvention provides a method for producing a therapeutic compositionenriched with full-length mRNA that encodes for an antigen from a herpessimplex virus, such as herpes simplex virus 1 or herpes simplex virus 2.In certain embodiments the present invention provides a method forproducing a therapeutic composition enriched with full-length mRNA thatencodes for an antigen from a human immunodeficiency virus, such ashuman immunodeficiency virus type 1 or human immunodeficiency virus type2. In certain embodiments the present invention provides a method forproducing a therapeutic composition enriched with full-length mRNA thatencodes for an antigen from a human metapneumovirus. In certainembodiments the present invention provides a method for producing atherapeutic composition enriched with full-length mRNA that encodes foran antigen from a human parainfluenza virus, such as human parainfluenzavirus type 1, human parainfluenza virus type 2, or human parainfluenzavirus type 3. In certain embodiments the present invention provides amethod for producing a therapeutic composition enriched with full-lengthmRNA that encodes for an antigen from malaria virus. In certainembodiments the present invention provides a method for producing atherapeutic composition enriched with full-length mRNA that encodes foran antigen from zika virus. In certain embodiments the present inventionprovides a method for producing a therapeutic composition enriched withfull-length mRNA that encodes for an antigen from chikungunya virus.

In certain embodiments the present invention provides a method forproducing a therapeutic composition enriched with full-length mRNA thatencodes for an antigen associated with a cancer of a subject oridentified from a cancer cell of a subject. In certain embodiments thepresent invention provides a method for producing a therapeuticcomposition enriched with full-length mRNA that encodes for an antigendetermined from a subject's own cancer cell, i.e., to provide apersonalized cancer vaccine. In certain embodiments the presentinvention provides a method for producing a therapeutic compositionenriched with full-length mRNA that encodes for an antigen expressedfrom a mutant KRAS gene.

In certain embodiments the present invention provides a method forproducing a therapeutic composition enriched with full-length mRNA thatencodes for an antibody. In certain embodiments, the antibody can be abi-specific antibody. In certain embodiments, the antibody can be partof a fusion protein. In certain embodiments the present inventionprovides a method for producing a therapeutic composition enriched withfull-length mRNA that encodes for an antibody to OX40. In certainembodiments the present invention provides a method for producing atherapeutic composition enriched with full-length mRNA that encodes foran antibody to VEGF. In certain embodiments the present inventionprovides a method for producing a therapeutic composition enriched withfull-length mRNA that encodes for an antibody to tissue necrosis factoralpha. In certain embodiments the present invention provides a methodfor producing a therapeutic composition enriched with full-length mRNAthat encodes for an antibody to CD3. In certain embodiments the presentinvention provides a method for producing a therapeutic compositionenriched with full-length mRNA that encodes for an antibody to CD19.

In certain embodiments the present invention provides a method forproducing a therapeutic composition enriched with full-length mRNA thatencodes for an immunomodulator. In certain embodiments the presentinvention provides a method for producing a therapeutic compositionenriched with full-length mRNA that encodes for Interleukin 12. Incertain embodiments the present invention provides a method forproducing a therapeutic composition enriched with full-length mRNA thatencodes for Interleukin 23. In certain embodiments the present inventionprovides a method for producing a therapeutic composition enriched withfull-length mRNA that encodes for Interleukin 36 gamma. In certainembodiments the present invention provides a method for producing atherapeutic composition enriched with full-length mRNA that encodes fora constitutively active variant of one or more stimulator of interferongenes (STING) proteins.

In certain embodiments the present invention provides a method forproducing a therapeutic composition enriched with full-length mRNA thatencodes for an endonuclease. In certain embodiments the presentinvention provides a method for producing a therapeutic compositionenriched with full-length mRNA that encodes for an RNA-guided DNAendonuclease protein, such as Cas 9 protein. In certain embodiments thepresent invention provides a method for producing a therapeuticcomposition enriched with full-length mRNA that encodes for ameganuclease protein. In certain embodiments the present inventionprovides a method for producing a therapeutic composition enriched withfull-length mRNA that encodes for a transcription activator-likeeffector nuclease protein. In certain embodiments the present inventionprovides a method for producing a therapeutic composition enriched withfull-length mRNA that encodes for a zinc finger nuclease protein.

In embodiments, exemplary therapeutic uses result from the delivery ofmRNA encoding a secreted protein. Accordingly, in embodiments, thecompositions and methods of the invention provide for delivery of mRNAencoding a secreted protein. In some embodiments, the compositions andmethods of the invention provide for delivery of mRNA encoding one ormore secreted proteins listed in Table 1; thus, compositions of theinvention may comprise an mRNA encoding a protein listed in Table 1 (ora homolog thereof) along with other components set out herein, andmethods of the invention may comprise preparing and/or administering acomposition comprising an mRNA encoding a protein listed in Table 1 (ora homolog thereof) along with other components set out herein.

In some embodiments, compositions and methods of the invention providefor the delivery of one or more nucleic acids that bind to or otherwiseact on an endogenous nucleic acid, such as endogenous mRNA or DNA, thatalter the transcription, translation, secretion, or action of one ormore proteins or genes listed in Table 1 (or a homolog thereof). Forexample, various RNAi nucleic acids bind to endogenous mRNA, miRNA, orother RNAs, while guide RNA (gRNA) and CRISPR RNA (crRNA) respectivelybind to DNA and act on DNA in the nucleus. Accordingly, in embodiments,the compositions and methods of the invention provide for delivery ofnucleic acids including one or more of RNAi nucleic acids, gRNA andcrRNA that interfere with the transcription, translation, secretion, oraction of one or more genes or proteins listed in Table 1 (or homologsthereof) along with other components set out herein.

TABLE 1 Secreted Proteins Uniprot ID Protein Name Gene Name A1E959Odontogenic ameloblast-associated protein ODAM A1KZ92 Peroxidasin-likeprotein PXDNL A1L453 Serine protease 38 PRSS38 A1L4H1 Soluble scavengerreceptor cysteine-rich domain- SSC5D containing protein SSC5D A2RUU4Colipase-like protein 1 CLPSL1 A2VDF0 Fucose mutarotase FUOM A2VEC9SCO-spondin SSPO A3KMH1 von Willebrand factor A domain-containing VWA8protein 8 A4D0S4 Laminin subunit beta-4 LAMB4 A4D1T9 Probable inactiveserine protease 37 PRSS37 A5D8T8 C-type lectin domain family 18 member ACLEC18A A6NC86 phospholipase A2 inhibitor and Ly6/PLAUR PINLYPdomain-containing protein A6NCI4 von Willebrand factor Adomain-containing VWA3A protein 3A A6ND01 Probable folate receptor deltaFOLR4 A6NDD2 Beta-defensin 108B-like A6NE02 BTB/POZ domain-containingprotein 17 BTBD17 A6NEF6 Growth hormone 1 GH1 A6NF02 NPIP-like proteinLOC730153 A6NFB4 HCG1749481, isoform CRA_k CSH1 A6NFZ4 Protein FAM24AFAM24A A6NG13 Glycosyltransferase 54 domain-containing protein A6NGN9IgLON family member 5 IGLON5 A6NHN0 Otolin-1 OTOL1 A6NHN6 Nuclear porecomplex-interacting protein-like 2 NPIPL2 A6NI73 Leukocyteimmunoglobulin-like receptor LILRA5 subfamily A member 5 A6NIT4Chorionic somatomammotropin hormone 2 CSH2 isoform 2 A6NJ69 IgA-inducingprotein homolog IGIP A6NKQ9 Choriogonadotropin subunit beta variant 1CGB1 A6NMZ7 Collagen alpha-6(VI) chain COL6A6 A6NNS2Dehydrogenase/reductase SDR family member 7C DHRS7C A6XGL2 Insulin Achain INS A8K0G1 Protein Wnt WNT7B A8K2U0 Alpha-2-macroglobulin-likeprotein 1 A2ML1 A8K7I4 Calcium-activated chloride channel regulator 1CLCA1 A8MTL9 Serpin-like protein HMSD HMSD A8MV23 Serpin E3 SERPINE3A8MZH6 Oocyte-secreted protein 1 homolog OOSP1 A8TX70 Collagenalpha-5(VI) chain COL6A5 B0ZBE8 Natriuretic peptide NPPA B1A4G9Somatotropin GH1 B1A4H2 HCG1749481, isoform CRA_d CSH1 B1A4H9 Chorionicsomatomammotropin hormone CSH2 B1AJZ6 Protein Wnt WNT4 B1AKI9 Isthmin-1ISM1 B2RNN3 Complement C1q and tumor necrosis factor- C1QTNF9B relatedprotein 9B B2RUY7 von Willebrand factor C domain-containing VWC2Lprotein 2-like B3GLJ2 Prostate and testis expressed protein 3 PATE3B4DI03 SEC11-like 3 (S. cerevisiae), isoform CRA_a SEC11L3 B4DJF9Protein Wnt WNT4 B4DUL4 SEC11-like 1 (S. cerevisiae), isoform CRA_dSEC11L1 B5MCC8 Protein Wnt WNT10B B8A595 Protein Wnt WNT7B B8A597Protein Wnt WNT7B B8A598 Protein Wnt WNT7B B9A064 Immunoglobulinlambda-like polypeptide 5 IGLL5 C9J3H3 Protein Wnt WNT10B C9J8I8 ProteinWnt WNT5A C9JAF2 Insulin-like growth factor II Ala-25 Del IGF2 C9JCI2Protein Wnt WNT10B C9JL84 HERV-H LTR-associating protein 1 HHLA1 C9JNR5Insulin A chain INS C9JUI2 Protein Wnt WNT2 D6RF47 Protein Wnt WNT8AD6RF94 Protein Wnt WNT8A E2RYF7 Protein PBMUCL2 HCG22 E5RFR1PENK(114-133) PENK E7EML9 Serine protease 44 PRSS44 E7EPC3 Protein WntWNT9B E7EVP0 Nociceptin PNOC E9PD02 Insulin-like growth factor I IGF1E9PH60 Protein Wnt WNT16 E9PJL6 Protein Wnt WNT11 F5GYM2 Protein WntWNT5B F5H034 Protein Wnt WNT5B F5H364 Protein Wnt WNT5B F5H7Q6 ProteinWnt WNT5B F8WCM5 Protein INS-IGF2 INS-IGF2 F8WDR1 Protein Wnt WNT2H0Y663 Protein Wnt WNT4 H0YK72 Signal peptidase complex catalyticsubunit SEC11A SEC11A H0YK83 Signal peptidase complex catalytic subunitSEC11A SEC11A H0YM39 Chorionic somatomammotropin hormone CSH2 H0YMT7Chorionic somatomammotropin hormone CSH1 H0YN17 Chorionicsomatomammotropin hormone CSH2 H0YNA5 Signal peptidase complex catalyticsubunit SEC11A SEC11A H0YNG3 Signal peptidase complex catalytic subunitSEC11A SEC11A H0YNX5 Signal peptidase complex catalytic subunit SEC11ASEC11A H7BZB8 Protein Wnt WNT10A H9KV56 Choriogonadotropin subunit betavariant 2 CGB2 I3L0L8 Protein Wnt WNT9B J3KNZ1 Choriogonadotropinsubunit beta variant 1 CGB1 J3KP00 Choriogonadotropin subunit beta CGB7J3QT02 Choriogonadotropin subunit beta variant 1 CGB1 O00175 C-C motifchemokine 24 CCL24 O00182 Galectin-9 LGALS9 O00187 Mannan-binding lectinserine protease 2 MASP2 O00230 Cortistatin CORT O00253 Agouti-relatedprotein AGRP O00270 12-(S)-hydroxy-5,8,10,14-eicosatetraenoic acid GPR31receptor O00292 Left-right determination factor 2 LEFTY2 O00294Tubby-related protein 1 TULP1 O00295 Tubby-related protein 2 TULP2O00300 Tumor necrosis factor receptor superfamily TNFRSF11B member 11BO00339 Matrilin-2 MATN2 O00391 Sulfhydryl oxidase 1 QSOX1 O00468 AgrinAGRN O00515 Ladinin-1 LAD1 O00533 Processed neural cell adhesionmolecule L1-like CHL1 protein O00584 Ribonuclease T2 RNASET2 O00585 C-Cmotif chemokine 21 CCL21 O00602 Ficolin-1 FCN1 O00622 Protein CYR61CYR61 O00626 MDC(5-69) CCL22 O00634 Netrin-3 NTN3 O00744 Protein Wnt-10bWNT10B O00755 Protein Wnt-7a WNT7A O14498 Immunoglobulin superfamilycontaining leucine- ISLR rich repeat protein O14511 Pro-neuregulin-2,membrane-bound isoform NRG2 O14594 Neurocan core protein NCAN O14625C-X-C motif chemokine 11 CXCL11 O14638 Ectonucleotide ENPP3pyrophosphatase/phosphodiesterase family member 3 O14656 Torsin-1A TOR1AO14657 Torsin-1B TOR1B O14786 Neuropilin-1 NRP1 O14788 Tumor necrosisfactor ligand superfamily member TNFSF11 11, membrane form O14791Apolipoprotein L1 APOL1 O14793 Growth/differentiation factor 8 MSTNO14904 Protein Wnt-9a WNT9A O14905 Protein Wnt-9b WNT9B O14944Proepiregulin EREG O14960 Leukocyte cell-derived chemotaxin-2 LECT2O15018 Processed PDZ domain-containing protein 2 PDZD2 O15041Semaphorin-3E SEMA3E O15072 A disintegrin and metalloproteinase withADAMTS3 thrombospondin motifs 3 O15123 Angiopoietin-2 ANGPT2 O15130Neuropeptide FF NPFF O15197 Ephrin type-B receptor 6 EPHB6 O15204 ADAMDEC 1 ADAMDEC1 O15230 Laminin subunit alpha-5 LAMA5 O15232 Matrilin-3MATN3 O15240 Neuroendocrine regulatory peptide-1 VGF O15263Beta-defensin 4A DEFB4A O15335 Chondroadherin CHAD O15393 Transmembraneprotease serine 2 catalytic chain TMPRSS2 O15444 C-C motif chemokine 25CCL25 O15467 C-C motif chemokine 16 CCL16 O15496 Group 10 secretoryphospholipase A2 PLA2G10 O15520 Fibroblast growth factor 10 FGF10 O15537Retinoschisin RS1 O43157 Plexin-B1 PLXNB1 O43184 Disintegrin andmetalloproteinase domain- ADAM12 containing protein 12 O43240Kallikrein-10 KLK10 O43278 Kunitz-type protease inhibitor 1 SPINT1O43320 Fibroblast growth factor 16 FGF16 O43323 Desert hedgehog proteinC-product DHH O43405 Cochlin COCH O43508 Tumor necrosis factor ligandsuperfamily member TNFSF12 12, membrane form O43555 Progonadoliberin-2GNRH2 O43557 Tumor necrosis factor ligand superfamily member TNFSF14 14,soluble form O43692 Peptidase inhibitor 15 PI15 O43699 Sialicacid-binding Ig-like lectin 6 SIGLEC6 O43820 Hyaluronidase-3 HYAL3O43827 Angiopoietin-related protein 7 ANGPTL7 O43852 Calumenin CALUO43854 EGF-like repeat and discoidin I-like domain- EDIL3 containingprotein 3 O43866 CD5 antigen-like CD5L O43897 Tolloid-like protein 1TLL1 O43915 Vascular endothelial growth factor D FIGF O43927 C-X-C motifchemokine 13 CXCL13 O60218 Aldo-keto reductase family 1 member B10AKR1B10 O60235 Transmembrane protease serine 11D TMPRSS11D O60258Fibroblast growth factor 17 FGF17 O60259 Kallikrein-8 KLK8 O60383Growth/differentiation factor 9 GDF9 O60469 Down syndrome cell adhesionmolecule DSCAM O60542 Persephin PSPN O60565 Gremlin-1 GREM1 O60575Serine protease inhibitor Kazal-type 4 SPINK4 O60676 Cystatin-8 CST8O60687 Sushi repeat-containing protein SRPX2 SRPX2 O60844 Zymogengranule membrane protein 16 ZG16 O60882 Matrix metalloproteinase-20MMP20 O60938 Keratocan KERA O75015 Low affinity immunoglobulin gamma Fcregion FCGR3B receptor III-B O75077 Disintegrin and metalloproteinasedomain- ADAM23 containing protein 23 O75093 Slit homolog 1 protein SLIT1O75094 Slit homolog 3 protein SLIT3 O75095 Multiple epidermal growthfactor-like domains MEGF6 protein 6 O75173 A disintegrin andmetalloproteinase with ADAMTS4 thrombospondin motifs 4 O75200 Nuclearpore complex-interacting protein-like 1 NPIPL1 O75339 Cartilageintermediate layer protein 1 C1 CILP O75354 Ectonucleoside triphosphatediphosphohydrolase 6 ENTPD6 O75386 Tubby-related protein 3 TULP3 O75398Deformed epidermal autoregulatory factor 1 DEAF1 homolog O75443Alpha-tectorin TECTA O75445 Usherin USH2A O75462 Cytokine receptor-likefactor 1 CRLF1 O75487 Glypican-4 GPC4 O75493 Carbonic anhydrase-relatedprotein 11 CA11 O75594 Peptidoglycan recognition protein 1 PGLYRP1O75596 C-type lectin domain family 3 member A CLEC3A O75610 Left-rightdetermination factor 1 LEFTY1 O75629 Protein CREG1 CREG1 O75636Ficolin-3 FCN3 O75711 Scrapie-responsive protein 1 SCRG1 O75715Epididymal secretory glutathione peroxidase GPX5 O75718Cartilage-associated protein CRTAP O75829 Chondrosurfactant proteinLECT1 O75830 Serpin I2 SERPINI2 O75882 Attractin ATRN O75888 Tumornecrosis factor ligand superfamily member TNFSF13 13 O75900 Matrixmetalloproteinase-23 MMP23A O75951 Lysozyme-like protein 6 LYZL6 O75973C1q-related factor C1QL1 O76038 Secretagogin SCGN O76061 Stanniocalcin-2STC2 O76076 WNT1-inducible-signaling pathway protein 2 WISP2 O76093Fibroblast growth factor 18 FGF18 O76096 Cystatin-F CST7 O94769Extracellular matrix protein 2 ECM2 O94813 Slit homolog 2 proteinC-product SLIT2 O94907 Dickkopf-related protein 1 DKK1 O94919Endonuclease domain-containing 1 protein ENDOD1 O94964 N-terminal formSOGA1 O95025 Semaphorin-3D SEMA3D O95084 Serine protease 23 PRSS23O95150 Tumor necrosis factor ligand superfamily member TNFSF15 15 O95156Neurexophilin-2 NXPH2 O95157 Neurexophilin-3 NXPH3 O95158Neurexophilin-4 NXPH4 O95388 WNT1-inducible-signaling pathway protein 1WISP1 O95389 WNT1-inducible-signaling pathway protein 3 WISP3 O95390Growth/differentiation factor 11 GDF11 O95393 Bone morphogenetic protein10 BMP 10 O95399 Urotensin-2 UTS2 O95407 Tumor necrosis factor receptorsuperfamily TNFRSF6B member 6B O95428 Papilin PAPLN O95445Apolipoprotein M APOM O95450 A disintegrin and metalloproteinase withADAMTS2 thrombospondin motifs 2 O95460 Matrilin-4 MATN4 O95467 LHALtetrapeptide GNAS O95631 Netrin-1 NTN1 O95633 Follistatin-relatedprotein 3 FSTL3 O95711 Lymphocyte antigen 86 LY86 O95715 C-X-C motifchemokine 14 CXCL14 O95750 Fibroblast growth factor 19 FGF19 O95760Interleukin-33 IL33 O95813 Cerberus CER1 O95841 Angiopoietin-relatedprotein 1 ANGPTL1 O95897 Noelin-2 OLFM2 O95925 Eppin EPPIN O95965Integrin beta-like protein 1 ITGBL1 O95967 EGF-containing fibulin-likeextracellular matrix EFEMP2 protein 2 O95968 Secretoglobin family 1Dmember 1 SCGB1D1 O95969 Secretoglobin family 1D member 2 SCGB1D2 O95970Leucine-rich glioma-inactivated protein 1 LGI1 O95972 Bone morphogeneticprotein 15 BMP15 O95994 Anterior gradient protein 2 homolog AGR2 O95998Interleukin-18-binding protein IL18BP O96009 Napsin-A NAPSA O96014Protein Wnt-11 WNT11 P00450 Ceruloplasmin CP P00451 Factor Villa lightchain F8 P00488 Coagulation factor XIII A chain F13A1 P00533 Epidermalgrowth factor receptor EGFR P00709 Alpha-lactalbumin LALBA P00734Prothrombin F2 P00738 Haptoglobin beta chain HP P00739Haptoglobin-related protein HPR P00740 Coagulation factor IXa heavychain F9 P00742 Factor X heavy chain F10 P00746 Complement factor D CFDP00747 Plasmin light chain B PLG P00748 Coagulation factor XIIa lightchain F12 P00749 Urokinase-type plasminogen activator long PLAU chain AP00750 Tissue-type plasminogen activator PLAT P00751 Complement factor BBa fragment CFB P00797 Renin REN P00973 2′-5′-oligoadenylate synthase 1OAS1 P00995 Pancreatic secretory trypsin inhibitor SPINK1 P01008Antithrombin-III SERPINC1 P01009 Alpha-1-antitrypsin SERPINA1 P01011Alpha-1-antichymotrypsin His-Pro-less SERPINA3 P01019 Angiotensin-1 AGTP01023 Alpha-2-macroglobulin A2M P01024 Acylation stimulating protein C3P01031 Complement C5 beta chain C5 P01033 Metalloproteinase inhibitor 1TIMP1 P01034 Cystatin-C CST3 P01036 Cystatin-S CST4 P01037 Cystatin-SNCST1 P01042 Kininogen-1 light chain KNG1 P01127 Platelet-derived growthfactor subunit B PDGFB P01135 Transforming growth factor alpha TGFAP01137 Transforming growth factor beta-1 TGFB1 P01138 Beta-nerve growthfactor NGF P01148 Gonadoliberin-1 GNRH1 P01160 Atrial natriuretic factorNPPA P01178 Oxytocin OXT P01185 Vasopressin-neurophysin 2-copeptin AVPP01189 Corticotropin POMC P01210 PENK(237-258) PENK P01213Alpha-neoendorphin PDYN P01215 Glycoprotein hormones alpha chain CGAP01222 Thyrotropin subunit beta TSHB P01225 Follitropin subunit betaFSHB P01229 Lutropin subunit beta LHB P01233 Choriogonadotropin subunitbeta CGB8 P01236 Prolactin PRL P01241 Somatotropin GH1 P01242 Growthhormone variant GH2 P01243 Chorionic somatomammotropin hormone CSH2P01258 Katacalcin CALCA P01266 Thyroglobulin TG P01270 Parathyroidhormone PTH P01275 Glucagon GCG P01282 Intestinal peptide PHM-27 VIPP01286 Somatoliberin GHRH P01298 Pancreatic prohormone PPY P01303C-flanking peptide of NPY NPY P01308 Insulin INS P01344 Insulin-likegrowth factor II IGF2 P01350 Big gastrin GAST P01374 Lymphotoxin-alphaLTA P01375 C-domain 1 TNF P01562 Interferon alpha-1/13 IFNA1 P01563Interferon alpha-2 IFNA2 P01566 Interferon alpha-10 IFNA10 P01567Interferon alpha-7 IFNA7 P01568 Interferon alpha-21 IFNA21 P01569Interferon alpha-5 IFNA5 P01570 Interferon alpha-14 IFNA14 P01571Interferon alpha-17 IFNA17 P01574 Interferon beta IFNB1 P01579Interferon gamma IFNG P01583 Interleukin-1 alpha IL1A P01584Interleukin-1 beta IL1B P01588 Erythropoietin EPO P01591 ImmunoglobulinJ chain IGJ P01732 T-cell surface glycoprotein CD8 alpha chain CD8AP01833 Polymeric immunoglobulin receptor PIGR P01857 Ig gamma-1 chain Cregion IGHG1 P01859 Ig gamma-2 chain C region IGHG2 P01860 Ig gamma-3chain C region IGHG3 P01861 Ig gamma-4 chain C region IGHG4 P01871 Ig muchain C region IGHM P01880 Ig delta chain C region IGHD P02452 Collagenalpha-1(I) chain COL1A1 P02458 Chondrocalcin COL2A1 P02461 Collagenalpha-1(III) chain COL3A1 P02462 Collagen alpha-1(IV) chain COL4A1P02647 Apolipoprotein A-I APOA1 P02649 Apolipoprotein E APOE P02652Apolipoprotein A-II APOA2 P02654 Apolipoprotein C-I APOC1 P02655Apolipoprotein C-II APOC2 P02656 Apolipoprotein C-III APOC3 P02671Fibrinogen alpha chain FGA P02675 Fibrinopeptide B FGB P02679 Fibrinogengamma chain FGG P02741 C-reactive protein CRP P02743 Serum amyloidP-component(1-203) APCS P02745 Complement C1q subcomponent subunit AC1QA P02746 Complement C1q subcomponent subunit B C1QB P02747 ComplementC1q subcomponent subunit C C1QC P02748 Complement component C9b C9P02749 Beta-2-glycoprotein 1 APOH P02750 Leucine-richalpha-2-glycoprotein LRG1 P02751 Ugl-Y2 FN1 P02753 Retinol-bindingprotein 4 RBP4 P02760 Trypstatin AMBP P02763 Alpha-1-acid glycoprotein 1ORM1 P02765 Alpha-2-HS-glycoprotein chain A AHSG P02766 TransthyretinTTR P02768 Serum albumin ALB P02771 Alpha-fetoprotein AFP P02774 VitaminD-binding protein GC P02775 Connective tissue-activating peptide IIIPPBP P02776 Platelet factor 4 PF4 P02778 CXCL10(1-73) CXCL10 P02786Transferrin receptor protein 1 TFRC P02787 Serotransferrin TF P02788Lactoferroxin-C LTF P02790 Hemopexin HPX P02808 Statherin STATH P02810Salivary acidic proline-rich phosphoprotein 1/2 PRH2 P02812 Basicsalivary proline-rich protein 2 PRB2 P02814 Peptide D1A SMR3B P02818Osteocalcin BGLAP P03950 Angiogenin ANG P03951 Coagulation factor XIaheavy chain F11 P03952 Plasma kallikrein KLKB1 P03956 27 kDainterstitial collagenase MMP1 P03971 Muellerian-inhibiting factor AMHP03973 Antileukoproteinase SLPI P04003 C4b-binding protein alpha chainC4BPA P04004 Somatomedin-B VTN P04054 Phospholipase A2 PLA2G1B P04085Platelet-derived growth factor subunit A PDGFA P04090 Relaxin A chainRLN2 P04114 Apolipoprotein B-100 APOB P04118 Colipase CLPS P04141Granulocyte-macrophage colony-stimulating CSF2 factor P04155 Trefoilfactor 1 TFF1 P04180 Phosphatidylcholine-sterol acyltransferase LCATP04196 Histidine-rich glycoprotein HRG P04217 Alpha-1B-glycoprotein A1BGP04275 von Willebrand antigen 2 VWF P04278 Sex hormone-binding globulinSHBG P04279 Alpha-inhibin-31 SEMG1 P04280 Basic salivary proline-richprotein 1 PRB1 P04628 Proto-oncogene Wnt-1 WNT1 P04745 Alpha-amylase 1AMY1A P04746 Pancreatic alpha-amylase AMY2A P04808 Prorelaxin H1 RLN1P05000 Interferon omega-1 IFNW1 P05013 Interferon alpha-6 IFNA6 P05014Interferon alpha-4 IFNA4 P05015 Interferon alpha-16 IFNA16 P05019Insulin-like growth factor I IGF1 P05060 GAWK peptide CHGB P05090Apolipoprotein D APOD P05109 Protein S100-A8 S100A8 P05111 Inhibin alphachain INHA P05112 Interleukin-4 IL4 P05113 Interleukin-5 IL5 P05120Plasminogen activator inhibitor 2 SERPINB2 P05121 Plasminogen activatorinhibitor 1 SERPINE1 P05154 Plasma serine protease inhibitor SERPINA5P05155 Plasma protease C1 inhibitor SERPING1 P05156 Complement factor Iheavy chain CFI P05160 Coagulation factor XIII B chain F13B P05161Ubiquitin-like protein ISG15 ISG15 P05230 Fibroblast growth factor 1FGF1 P05231 Interleukin-6 IL6 P05305 Big endothelin-1 EDN1 P05408C-terminal peptide SCG5 P05451 Lithostathine-1-alpha REG1A P05452Tetranectin CLEC3B P05543 Thyroxine-binding globulin SERPINA7 P05814Beta-casein CSN2 P05997 Collagen alpha-2(V) chain COL5A2 P06276Cholinesterase BCHE P06307 Cholecystokinin-12 CCK P06396 Gelsolin GSNP06681 Complement C2 C2 P06702 Protein S100-A9 S100A9 P06727Apolipoprotein A-IV APOA4 P06734 Low affinity immunoglobulin epsilon Fcreceptor FCER2 soluble form P06744 Glucose-6-phosphate isomerase GPIP06850 Corticoliberin CRH P06858 Lipoprotein lipase LPL P06881Calcitonin gene-related peptide 1 CALCA P07093 Glia-derived nexinSERPINE2 P07098 Gastric triacylglycerol lipase LIPF P07225 VitaminK-dependent protein S PROS1 P07237 Protein disulfide-isomerase P4HBP07288 Prostate-specific antigen KLK3 P07306 Asialoglycoprotein receptor1 ASGR1 P07355 Annexin A2 ANXA2 P07357 Complement component C8 alphachain C8A P07358 Complement component C8 beta chain C8B P07360Complement component C8 gamma chain C8G P07477 Alpha-trypsin chain 2PRSS1 P07478 Trypsin-2 PRSS2 P07492 Neuromedin-C GRP P07498 Kappa-caseinCSN3 P07585 Decorin DCN P07911 Uromodulin UMOD P07942 Laminin subunitbeta-1 LAMB1 P07988 Pulmonary surfactant-associated protein B SFTPBP07998 Ribonuclease pancreatic RNASE1 P08118 Beta-microseminoproteinMSMB P08123 Collagen alpha-2(I) chain COL1A2 P08185Corticosteroid-binding globulin SERPINA6 P08217 Chymotrypsin-likeelastase family member 2A CELA2A P08218 Chymotrypsin-like elastasefamily member 2B CELA2B P08253 72 kDa type IV collagenase MMP2 P08254Stromelysin-1 MMP3 P08294 Extracellular superoxide dismutase [Cu—Zn]SOD3 P08476 Inhibin beta A chain INHBA P08493 Matrix Gla protein MGPP08572 Collagen alpha-2(IV) chain COL4A2 P08581 Hepatocyte growth factorreceptor MET P08603 Complement factor H CFH P08620 Fibroblast growthfactor 4 FGF4 P08637 Low affinity immunoglobulin gamma Fc region FCGR3Areceptor III-A P08697 Alpha-2-antiplasmin SERPINF2 P08700 Interleukin-3IL3 P08709 Coagulation factor VII F7 P08833 Insulin-like growthfactor-binding protein 1 IGFBP1 P08887 Interleukin-6 receptor subunitalpha IL6R P08949 Neuromedin-B-32 NMB P08F94 Fibrocystin PKHD1 P09038Fibroblast growth factor 2 FGF2 P09228 Cystatin-SA CST2 P09237Matrilysin MMP7 P09238 Stromelysin-2 MMP10 P09341 Growth-regulated alphaprotein CXCL1 P09382 Galectin-1 LGALS1 P09466 Glycodelin PAEP P09486SPARC SPARC P09529 Inhibin beta B chain INHBB P09544 Protein Wnt-2 WNT2P09603 Processed macrophage colony-stimulating factor 1 CSF1 P09681Gastric inhibitory polypeptide GIP P09683 Secretin SCT P09919Granulocyte colony-stimulating factor CSF3 P0C091 FRAS1-relatedextracellular matrix protein 3 FREM3 P0C0L4 C4d-A C4A P0C0L5 ComplementC4-B alpha chain C4B P0C0P6 Neuropeptide S NPS P0C7L1 Serine proteaseinhibitor Kazal-type 8 SPINK8 P0C862 Complement C1q and tumor necrosisfactor- C1QTNF9 related protein 9A P0C8F1 Prostate and testis expressedprotein 4 PATE4 P0CG01 Gastrokine-3 GKN3P P0CG36 Cryptic family protein1B CFC1B P0CG37 Cryptic protein CFC1 P0CJ68 Humanin-like protein 1MTRNR2L1 P0CJ69 Humanin-like protein 2 MTRNR2L2 P0CJ70 Humanin-likeprotein 3 MTRNR2L3 P0CJ71 Humanin-like protein 4 MTRNR2L4 P0CJ72Humanin-like protein 5 MTRNR2L5 P0CJ73 Humanin-like protein 6 MTRNR2L6P0CJ74 Humanin-like protein 7 MTRNR2L7 P0CJ75 Humanin-like protein 8MTRNR2L8 P0CJ76 Humanin-like protein 9 MTRNR2L9 P0CJ77 Humanin-likeprotein 10 MTRNR2L10 P0DJD7 Pepsin A-4 PGA4 P0DJD8 Pepsin A-3 PGA3P0DJD9 Pepsin A-5 PGA5 P0DJI8 Amyloid protein A SAA1 P0DJI9 Serumamyloid A-2 protein SAA2 P10082 Peptide YY(3-36) PYY P10092 Calcitoningene-related peptide 2 CALCB P10124 Serglycin SRGN P10145 MDNCF-a IL8P10147 MIP-1-alpha(4-69) CCL3 P10163 Peptide P-D PRB4 P10451 OsteopontinSPP1 P10599 Thioredoxin TXN P10600 Transforming growth factor beta-3TGFB3 P10643 Complement component C7 C7 P10645 Vasostatin-2 CHGA P10646Tissue factor pathway inhibitor TFPI P10720 Platelet factor 4variant(4-74) PF4V1 P10745 Retinol-binding protein 3 RBP3 P10767Fibroblast growth factor 6 FGF6 P10909 Clusterin alpha chain CLU P10912Growth hormone receptor GHR P10915 Hyaluronan and proteoglycan linkprotein 1 HAPLN1 P10966 T-cell surface glycoprotein CD8 beta chain CD8BP10997 Islet amyloid polypeptide IAPP P11047 Laminin subunit gamma-1LAMC1 P11150 Hepatic triacylglycerol lipase LIPC P11226 Mannose-bindingprotein C MBL2 P11464 Pregnancy-specific beta-1-glycoprotein 1 PSG1P11465 Pregnancy-specific beta-1-glycoprotein 2 PSG2 P11487 Fibroblastgrowth factor 3 FGF3 P11597 Cholesteryl ester transfer protein CETPP11684 Uteroglobin SCGB1A1 P11686 Pulmonary surfactant-associatedprotein C SFTPC P12034 Fibroblast growth factor 5 FGF5 P12107 Collagenalpha-1(XI) chain COL11A1 P12109 Collagen alpha-1(VI) chain COL6A1P12110 Collagen alpha-2(VI) chain COL6A2 P12111 Collagen alpha-3(VI)chain COL6A3 P12259 Coagulation factor V F5 P12272 PTHrP[1-36] PTHLHP12273 Prolactin-inducible protein PIP P12544 Granzyme A GZMA P12643Bone morphogenetic protein 2 BMP2 P12644 Bone morphogenetic protein 4BMP4 P12645 Bone morphogenetic protein 3 BMP3 P12724 Eosinophil cationicprotein RNASE3 P12821 Angiotensin-converting enzyme, soluble form ACEP12838 Neutrophil defensin 4 DEFA4 P12872 Motilin MLN P13232Interleukin-7 IL7 P13236 C-C motif chemokine 4 CCL4 P13284Gamma-interferon-inducible lysosomal thiol IFI30 reductase P13500 C-Cmotif chemokine 2 CCL2 P13501 C-C motif chemokine 5 CCL5 P13521Secretogranin-2 SCG2 P13591 Neural cell adhesion molecule 1 NCAM1 P13611Versican core protein VCAN P13671 Complement component C6 C6 P13688Carcinoembryonic antigen-related cell adhesion CEACAM1 molecule 1 P13725Oncostatin-M OSM P13726 Tissue factor F3 P13727 Eosinophil granule majorbasic protein PRG2 P13942 Collagen alpha-2(XI) chain COL11A2 P13987 CD59glycoprotein CD59 P14138 Endothelin-3 EDN3 P14174 Macrophage migrationinhibitory factor MIF P14207 Folate receptor beta FOLR2 P14222Perforin-1 PRF1 P14543 Nidogen-1 NID1 P14555 Phospholipase A2, membraneassociated PLA2G2A P14625 Endoplasmin HSP90B1 P14735 Insulin-degradingenzyme IDE P14778 Interleukin-1 receptor type 1, soluble form IL1R1P14780 82 kDa matrix metalloproteinase-9 MMP9 P15018 Leukemia inhibitoryfactor LIF P15085 Carboxypeptidase A1 CPA1 P15086 Carboxypeptidase BCPB1 P15151 Poliovirus receptor PVR P15169 Carboxypeptidase N catalyticchain CPN1 P15248 Interleukin-9 IL9 P15291 N-acetyllactosamine synthaseB4GALT1 P15309 PAPG9 ACPP P15328 Folate receptor alpha FOLR1 P15374Ubiquitin carboxyl-terminal hydrolase isozyme L3 UCHL3 P15502 ElastinELN P15509 Granulocyte-macrophage colony-stimulating CSF2RA factorreceptor subunit alpha P15515 Histatin-1 HTN1 P15516His3-(31-51)-peptide HTN3 P15692 Vascular endothelial growth factor AVEGFA P15814 Immunoglobulin lambda-like polypeptide 1 IGLL1 P15907Beta-galactoside alpha-2,6-sialyltransferase 1 ST6GAL1 P15941 Mucin-1subunit beta MUC1 P16035 Metalloproteinase inhibitor 2 TIMP2 P16112Aggrecan core protein 2 ACAN P16233 Pancreatic triacylglycerol lipasePNLIP P16442 Histo-blood group ABO system transferase ABO P16471Prolactin receptor PRLR P16562 Cysteine-rich secretory protein 2 CRISP2P16619 C-C motif chemokine 3-like 1 CCL3L1 P16860 BNP(3-29) NPPB P16870Carboxypeptidase E CPE P16871 Interleukin-7 receptor subunit alpha IL7RP17213 Bactericidal permeability-increasing protein BPI P17538Chymotrypsinogen B CTRB1 P17931 Galectin-3 LGALS3 P17936 Insulin-likegrowth factor-binding protein 3 IGFBP3 P17948 Vascular endothelialgrowth factor receptor 1 FLT1 P18065 Insulin-like growth factor-bindingprotein 2 IGFBP2 P18075 Bone morphogenetic protein 7 BMP7 P18428Lipopolysaccharide-binding protein LBP P18509 PACAP-related peptideADCYAP1 P18510 Interleukin-1 receptor antagonist protein IL1RN P18827Syndecan-1 SDC1 P19021 Peptidylglycine alpha-hydroxylating PAMmonooxygenase P19235 Erythropoietin receptor EPOR P19438 Tumor necrosisfactor-binding protein 1 TNFRSF1A P19652 Alpha-1-acid glycoprotein 2ORM2 P19801 Amiloride-sensitive amine oxidase [copper- ABP1 containing]P19823 Inter-alpha-trypsin inhibitor heavy chain H2 ITIH2 P19827Inter-alpha-trypsin inhibitor heavy chain H1 ITIH1 P19835 Bilesalt-activated lipase CEL P19875 C-X-C motif chemokine 2 CXCL2 P19876C-X-C motif chemokine 3 CXCL3 P19883 Follistatin FST P19957 Elafin PI3P19961 Alpha-amylase 2B AMY2B P20061 Transcobalamin-1 TCN1 P20062Transcobalamin-2 TCN2 P20142 Gastricsin PGC P20155 Serine proteaseinhibitor Kazal-type 2 SPINK2 P20231 Tryptase beta-2 TPSB2 P20333 Tumornecrosis factor receptor superfamily TNFRSF1B member 1B P20366 SubstanceP TAC1 P20382 Melanin-concentrating hormone PMCH P20396 Thyroliberin TRHP20742 Pregnancy zone protein PZP P20774 Mimecan OGN P20783Neurotrophin-3 NTF3 P20800 Endothelin-2 EDN2 P20809 Interleukin-11 IL11P20827 Ephrin-A1 EFNA1 P20849 Collagen alpha-1(IX) chain COL9A1 P20851C4b-binding protein beta chain C4BPB P20908 Collagen alpha-1(V) chainCOL5A1 P21128 Poly(U)-specific endoribonuclease ENDOU P21246Pleiotrophin PTN P21583 Kit ligand KITLG P21741 Midkine MDK P21754 Zonapellucida sperm-binding protein 3 ZP3 P21781 Fibroblast growth factor 7FGF7 P21802 Fibroblast growth factor receptor 2 FGFR2 P21810 BiglycanBGN P21815 Bone sialoprotein 2 IBSP P21860 Receptor tyrosine-proteinkinase erbB-3 ERBB3 P21941 Cartilage matrix protein MATN1 P22003 Bonemorphogenetic protein 5 BMP5 P22004 Bone morphogenetic protein 6 BMP6P22079 Lactoperoxidase LPO P22105 Tenascin-X TNXB P22301 Interleukin-10IL10 P22303 Acetylcholinesterase ACHE P22352 Glutathione peroxidase 3GPX3 P22362 C-C motif chemokine 1 CCL1 P22455 Fibroblast growth factorreceptor 4 FGFR4 P22466 Galanin message-associated peptide GAL P22692Insulin-like growth factor-binding protein 4 IGFBP4 P22749 GranulysinGNLY P22792 Carboxypeptidase N subunit 2 CPN2 P22891 Vitamin K-dependentprotein Z PROZ P22894 Neutrophil collagenase MMP8 P23142 Fibulin-1 FBLN1P23280 Carbonic anhydrase 6 CA6 P23352 Anosmin-1 KAL1 P23435Cerebellin-1 CBLN1 P23560 Brain-derived neurotrophic factor BDNF P23582C-type natriuretic peptide NPPC P23946 Chymase CMA1 P24043 Lamininsubunit alpha-2 LAMA2 P24071 Immunoglobulin alpha Fc receptor FCARP24347 Stromelysin-3 MMP11 P24387 Corticotropin-releasing factor-bindingprotein CRHBP P24592 Insulin-like growth factor-binding protein 6 IGFBP6P24593 Insulin-like growth factor-binding protein 5 IGFBP5 P24821Tenascin TNC P24855 Deoxyribonuclease-1 DNASE1 P25067 Collagenalpha-2(VIII) chain COL8A2 P25311 Zinc-alpha-2-glycoprotein AZGP1 P25391Laminin subunit alpha-1 LAMA1 P25445 Tumor necrosis factor receptorsuperfamily FAS member 6 P25940 Collagen alpha-3(V) chain COL5A3 P25942Tumor necrosis factor receptor superfamily CD40 member 5 P26022Pentraxin-related protein PTX3 PTX3 P26927 Hepatocyte growth factor-likeprotein beta chain MST1 P27169 Serum paraoxonase/arylesterase 1 PON1P27352 Gastric intrinsic factor GIF P27487 Dipeptidyl peptidase 4membrane form DPP4 P27539 Embryonic growth/differentiation factor 1 GDF1P27658 Vastatin COL8A1 P27797 Calreticulin CALR P27918 Properdin CFPP28039 Acyloxyacyl hydrolase AOAH P28300 Protein-lysine 6-oxidase LOXP28325 Cystatin-D CST5 P28799 Granulin-1 GRN P29122 Proproteinconvertase subtilisin/kexin type 6 PCSK6 P29279 Connective tissue growthfactor CTGF P29320 Ephrin type-A receptor 3 EPHA3 P29400 Collagenalpha-5(IV) chain COL4A5 P29459 Interleukin-12 subunit alpha IL12AP29460 Interleukin-12 subunit beta IL12B P29508 Serpin B3 SERPINB3P29622 Kallistatin SERPINA4 P29965 CD40 ligand, soluble form CD40LGP30990 Neurotensin/neuromedin N NTS P31025 Lipocalin-1 LCN1 P31151Protein S100-A7 S100A7 P31371 Fibroblast growth factor 9 FGF9 P31431Syndecan-4 SDC4 P31947 14-3-3 protein sigma SFN P32455Interferon-induced guanylate-binding protein 1 GBP1 P32881 Interferonalpha-8 IFNA8 P34096 Ribonuclease 4 RNASE4 P34130 Neurotrophin-4 NTF4P34820 Bone morphogenetic protein 8B BMP8B P35030 Trypsin-3 PRSS3 P35052Secreted glypican-1 GPC1 P35070 Betacellulin BTC P35225 Interleukin-13IL13 P35247 Pulmonary surfactant-associated protein D SFTPD P35318 ADMADM P35542 Serum amyloid A-4 protein SAA4 P35555 Fibrillin-1 FBN1 P35556Fibrillin-2 FBN2 P35625 Metalloproteinase inhibitor 3 TIMP3 P35858Insulin-like growth factor-binding protein complex IGFALS acid labilesubunit P35916 Vascular endothelial growth factor receptor 3 FLT4 P35968Vascular endothelial growth factor receptor 2 KDR P36222Chitinase-3-like protein 1 CHI3L1 P36952 Serpin B5 SERPINB5 P36955Pigment epithelium-derived factor SERPINF1 P36980 Complement factorH-related protein 2 CFHR2 P39059 Collagen alpha-1(XV) chain COL15A1P39060 Collagen alpha-1(XVIII) chain COL18A1 P39877 Calcium-dependentphospholipase A2 PLA2G5 P39900 Macrophage metalloelastase MMP12 P39905Glial cell line-derived neurotrophic factor GDNF P40225 ThrombopoietinTHPO P40967 M-alpha PMEL P41159 Leptin LEP P41221 Protein Wnt-5a WNT5AP41222 Prostaglandin-H2 D-isomerase PTGDS P41271 Neuroblastomasuppressor of tumorigenicity 1 NBL1 P41439 Folate receptor gamma FOLR3P42127 Agouti-signaling protein ASIP P42702 Leukemia inhibitory factorreceptor LIFR P42830 ENA-78(9-78) CXCL5 P43026 Growth/differentiationfactor 5 GDF5 P43251 Biotinidase BTD P43652 Afamin AFM P45452Collagenase 3 MMP13 P47710 Casoxin-D CSN1S1 P47929 Galectin-7 LGALS7BP47972 Neuronal pentraxin-2 NPTX2 P47989 Xanthine oxidase XDH P47992Lymphotactin XCL1 P48023 Tumor necrosis factor ligand superfamily memberFASLG 6, membrane form P48052 Carboxypeptidase A2 CPA2 P48061 Stromalcell-derived factor 1 CXCL12 P48304 Lithostathine-1-beta REG1B P48307Tissue factor pathway inhibitor 2 TFPI2 P48357 Leptin receptor LEPRP48594 Serpin B4 SERPINB4 P48645 Neuromedin-U-25 NMU P48740Mannan-binding lectin serine protease 1 MASP1 P48745 Protein NOV homologNOV P48960 CD97 antigen subunit beta CD97 P49223 Kunitz-type proteaseinhibitor 3 SPINT3 P49747 Cartilage oligomeric matrix protein COMPP49763 Placenta growth factor PGF P49765 Vascular endothelial growthfactor B VEGFB P49767 Vascular endothelial growth factor C VEGFC P49771Fms-related tyrosine kinase 3 ligand FLT3LG P49862 Kallikrein-7 KLK7P49863 Granzyme K GZMK P49908 Selenoprotein P SEPP1 P49913 Antibacterialprotein FALL-39 CAMP P50607 Tubby protein homolog TUB P51124 Granzyme MGZMM P51512 Matrix metalloproteinase-16 MMP16 P51654 Glypican-3 GPC3P51671 Eotaxin CCL11 P51884 Lumican LUM P51888 Prolargin PRELP P52798Ephrin-A4 EFNA4 P52823 Stanniocalcin-1 STC1 P53420 Collagen alpha-4(IV)chain COL4A4 P53621 Coatomer subunit alpha COPA P54108 Cysteine-richsecretory protein 3 CRISP3 P54315 Pancreatic lipase-related protein 1PNLIPRP1 P54317 Pancreatic lipase-related protein 2 PNLIPRP2 P54793Arylsulfatase F ARSF P55000 Secreted Ly-6/uPAR-related protein 1 SLURP 1P55001 Microfibrillar-associated protein 2 MFAP2 P55056 ApolipoproteinC-IV APOC4 P55058 Phospholipid transfer protein PLTP P55075 Fibroblastgrowth factor 8 FGF8 P55081 Microfibrillar-associated protein 1 MFAP1P55083 Microfibril-associated glycoprotein 4 MFAP4 P55107 Bonemorphogenetic protein 3B GDF10 P55145 Mesencephalic astrocyte-derivedneurotrophic MANF factor P55259 Pancreatic secretory granule membranemajor GP2 glycoprotein GP2 P55268 Laminin subunit beta-2 LAMB2 P55773CCL23(30-99) CCL23 P55774 C-C motif chemokine 18 CCL18 P55789 FAD-linkedsulfhydryl oxidase ALR GFER P56703 Proto-oncogene Wnt-3 WNT3 P56704Protein Wnt-3a WNT3A P56705 Protein Wnt-4 WNT4 P56706 Protein Wnt-7bWNT7B P56730 Neurotrypsin PRSS12 P56851 Epididymal secretory proteinE3-beta EDDM3B P56975 Neuregulin-3 NRG3 P58062 Serine protease inhibitorKazal-type 7 SPINK7 P58215 Lysyl oxidase homolog 3 LOXL3 P58294Prokineticin-1 PROK1 P58335 Anthrax toxin receptor 2 ANTXR2 P58397 Adisintegrin and metalloproteinase with ADAMTS12 thrombospondin motifs 12P58417 Neurexophilin-1 NXPH1 P58499 Protein FAM3B FAM3B P59510 Adisintegrin and metalloproteinase with ADAMTS20 thrombospondin motifs 20P59665 Neutrophil defensin 1 DEFA1B P59666 Neutrophil defensin 3 DEFA3P59796 Glutathione peroxidase 6 GPX6 P59826 BPI fold-containing family Bmember 3 BPIFB3 P59827 BPI fold-containing family B member 4 BPIFB4P59861 Beta-defensin 131 DEFB131 P60022 Beta-defensin 1 DEFB1 P60153Inactive ribonuclease-like protein 9 RNASE9 P60827 Complement C1q tumornecrosis factor-related C1QTNF8 protein 8 P60852 Zona pellucidasperm-binding protein 1 ZP1 P60985 Keratinocytedifferentiation-associated protein KRTDAP P61109 Kidneyandrogen-regulated protein KAP P61278 Somatostatin-14 SST P61366Osteocrin OSTN P61626 Lysozyme C LYZ P61769 Beta-2-microglobulin B2MP61812 Transforming growth factor beta-2 TGFB2 P61916 Epididymalsecretory protein E1 NPC2 P62502 Epididymal-specific lipocalin-6 LCN6P62937 Peptidyl-prolyl cis-trans isomerase A PPIA P67809Nuclease-sensitive element-binding protein 1 YBX1 P67812 Signalpeptidase complex catalytic subunit SEC11A SEC11A P78310 Coxsackievirusand adenovirus receptor CXADR P78333 Secreted glypican-5 GPC5 P78380Oxidized low-density lipoprotein receptor 1 OLR1 P78423 Processedfractalkine CX3CL1 P78509 Reelin RELN P78556 CCL20(2-70) CCL20 P80075MCP-2(6-76) CCL8 P80098 C-C motif chemokine 7 CCL7 P80108Phosphatidylinositol-glycan-specific GPLD1 phospholipase D P80162 C-X-Cmotif chemokine 6 CXCL6 P80188 Neutrophil gelatinase-associatedlipocalin LCN2 P80303 Nucleobindin-2 NUCB2 P80511 Calcitermin S100A12P81172 Hepcidin-25 HAMP P81277 Prolactin-releasing peptide PRLH P81534Beta-defensin 103 DEFB103A P81605 Dermcidin DCD P82279 Protein crumbshomolog 1 CRB1 P82987 ADAMTS-like protein 3 ADAMTSL3 P83105 Serineprotease HTRA4 HTRA4 P83110 Serine protease HTRA3 HTRA3 P83859Orexigenic neuropeptide QRFP QRFP P98088 Mucin-5AC MUC5AC P98095Fibulin-2 FBLN2 P98160 Basement membrane-specific heparan sulfate HSPG2proteoglycan core protein P98173 Protein FAM3A FAM3A Q00604 Norrin NDPQ00796 Sorbitol dehydrogenase SORD Q00887 Pregnancy-specificbeta-1-glycoprotein 9 PSG9 Q00888 Pregnancy-specific beta-1-glycoprotein4 PSG4 Q00889 Pregnancy-specific beta-1-glycoprotein 6 PSG6 Q01523HD5(56-94) DEFA5 Q01524 Defensin-6 DEFA6 Q01955 Collagen alpha-3(IV)chain COL4A3 Q02297 Pro-neuregulin-1, membrane-bound isoform NRG1 Q02325Plasminogen-like protein B PLGLB1 Q02383 Semenogelin-2 SEMG2 Q02388Collagen alpha-1(VII) chain COL7A1 Q02505 Mucin-3A MUC3A Q02509Otoconin-90 OC90 Q02747 Guanylin GUCA2A Q02763 Angiopoietin-1 receptorTEK Q02817 Mucin-2 MUC2 Q02985 Complement factor H-related protein 3CFHR3 Q03167 Transforming growth factor beta receptor type 3 TGFBR3Q03403 Trefoil factor 2 TFF2 Q03405 Urokinase plasminogen activatorsurface receptor PLAUR Q03591 Complement factor H-related protein 1CFHR1 Q03692 Collagen alpha-1(X) chain COL10A1 Q04118 Basic salivaryproline-rich protein 3 PRB3 Q04756 Hepatocyte growth factor activatorshort chain HGFAC Q04900 Sialomucin core protein 24 CD164 Q05315Eosinophil lysophospholipase CLC Q05707 Collagen alpha-1 (XIV) chainCOL14A1 Q05996 Processed zona pellucida sperm-binding protein 2 ZP2Q06033 Inter-alpha-trypsin inhibitor heavy chain H3 ITIH3 Q06141Regenerating islet-derived protein 3-alpha REG3A Q06828 FibromodulinFMOD Q07092 Collagen alpha-1(XVI) chain COL16A1 Q07325 C-X-C motifchemokine 9 CXCL9 Q07507 Dermatopontin DPT Q075Z2 Binder of spermprotein homolog 1 BSPH1 Q07654 Trefoil factor 3 TFF3 Q07699 Sodiumchannel subunit beta-1 SCN1B Q08345 Epithelial discoidindomain-containing receptor 1 DDR1 Q08380 Galectin-3-binding proteinLGALS3BP Q08397 Lysyl oxidase homolog 1 LOXL1 Q08431 Lactadherin MFGE8Q08629 Testican-1 SPOCK1 Q08648 Sperm-associated antigen 11B SPAG11BQ08830 Fibrinogen-like protein 1 FGL1 Q10471 PolypeptideN-acetylgalactosaminyltransferase 2 GALNT2 Q10472 PolypeptideN-acetylgalactosaminyltransferase 1 GALNT1 Q11201CMP-N-acetylneuraminate-beta-galactosamide- ST3GAL1alpha-2,3-sialyltransferase 1 Q11203CMP-N-acetylneuraminate-beta-1,4-galactoside ST3GAL3alpha-2,3-sialyltransferase Q11206CMP-N-acetylneuraminate-beta-galactosamide- ST3GAL4alpha-2,3-sialyltransferase 4 Q12794 Hyaluronidase-1 HYAL1 Q12805EGF-containing fibulin-like extracellular matrix EFEMP1 protein 1 Q12836Zona pellucida sperm-binding protein 4 ZP4 Q12841 Follistatin-relatedprotein 1 FSTL1 Q12904 Aminoacyl tRNA synthase complex-interacting AIMP1multifunctional protein 1 Q13018 Soluble secretory phospholipase A2receptor PLA2R1 Q13072 B melanoma antigen 1 BAGE Q13093Platelet-activating factor acetylhydrolase PLA2G7 Q13103 Secretedphosphoprotein 24 SPP2 Q13162 Peroxiredoxin-4 PRDX4 Q13201 Plateletglycoprotein Ia* MMRN1 Q13214 Semaphorin-3B SEMA3B Q13219 Pappalysin-1PAPPA Q13231 Chitotriosidase-1 CHIT1 Q13253 Noggin NOG Q13261Interleukin-15 receptor subunit alpha IL15RA Q13275 Semaphorin-3F SEMA3FQ13291 Signaling lymphocytic activation molecule SLAMF1 Q13316 Dentinmatrix acidic phosphoprotein 1 DMP1 Q13361 Microfibrillar-associatedprotein 5 MFAP5 Q13410 Butyrophilin subfamily 1 member A1 BTN1A1 Q13421Mesothelin, cleaved form MSLN Q13429 Insulin-like growth factor I IGF-IQ13443 Disintegrin and metalloproteinase domain- ADAM9 containingprotein 9 Q13519 Neuropeptide 1 PNOC Q13751 Laminin subunit beta-3 LAMB3Q13753 Laminin subunit gamma-2 LAMC2 Q13790 Apolipoprotein F APOF Q13822Ectonucleotide ENPP2 pyrophosphatase/phosphodiesterase family member 2Q14031 Collagen alpha-6(IV) chain COL4A6 Q14050 Collagen alpha-3(IX)chain COL9A3 Q14055 Collagen alpha-2(IX) chain COL9A2 Q14112 Nidogen-2NID2 Q14114 Low-density lipoprotein receptor-related protein 8 LRP8Q14118 Dystroglycan DAG1 Q14314 Fibroleukin FGL2 Q14393 Growtharrest-specific protein 6 GAS6 Q14406 Chorionic somatomammotropinhormone-like 1 CSHL1 Q14507 Epididymal secretory protein E3-alpha EDDM3AQ14508 WAP four-disulfide core domain protein 2 WFDC2 Q14512 Fibroblastgrowth factor-binding protein 1 FGFBP1 Q14515 SPARC-like protein 1SPARCL1 Q14520 Hyaluronan-binding protein 2 27 kDa light chain HABP2Q14563 Semaphorin-3A SEMA3A Q14623 Indian hedgehog protein IHH Q14624Inter-alpha-trypsin inhibitor heavy chain H4 ITIH4 Q14667 UPF0378protein KIAA0100 KIAA0100 Q14703 Membrane-bound transcription factorsite-1 MBTPS1 protease Q14766 Latent-transforming growth factorbeta-binding LTBP1 protein 1 Q14767 Latent-transforming growth factorbeta-binding LTBP2 protein 2 Q14773 Intercellular adhesion molecule 4ICAM4 Q14993 Collagen alpha-1(XIX) chain COL19A1 Q14CN2Calcium-activated chloride channel regulator 4, CLCA4 110 kDa formQ15046 Lysine--tRNA ligase KARS Q15063 Periostin POSTN Q15109 Advancedglycosylation end product-specific AGER receptor Q15113 ProcollagenC-endopeptidase enhancer 1 PCOLCE Q15166 Serum paraoxonase/lactonase 3PON3 Q15195 Plasminogen-like protein A PLGLA Q15198 Platelet-derivedgrowth factor receptor-like protein PDGFRL Q15223 Poliovirusreceptor-related protein 1 PVRL1 Q15238 Pregnancy-specificbeta-1-glycoprotein 5 PSG5 Q15363 Transmembrane emp24 domain-containingprotein 2 TMED2 Q15375 Ephrin type-A receptor 7 EPHA7 Q15389Angiopoietin-1 ANGPT1 Q15465 Sonic hedgehog protein SHH Q15485 Ficolin-2FCN2 Q15517 Corneodesmosin CDSN Q15582 Transforming growthfactor-beta-induced protein TGFBI ig-h3 Q15661 Tryptase alpha/beta-1TPSAB1 Q15726 Metastin KISS1 Q15782 Chitinase-3-like protein 2 CHI3L2Q15828 Cystatin-M CST6 Q15846 Clusterin-like protein 1 CLUL1 Q15848Adiponectin ADIPOQ Q16206 Protein disulfide-thiol oxidoreductase ENOX2Q16270 Insulin-like growth factor-binding protein 7 IGFBP7 Q16363Laminin subunit alpha-4 LAMA4 Q16378 Proline-rich protein 4 PRR4 Q16557Pregnancy-specific beta-1-glycoprotein 3 PSG3 Q16568 CART(42-89) CARTPTQ16610 Extracellular matrix protein 1 ECM1 Q16619 Cardiotrophin-1 CTF1Q16623 Syntaxin-1A STX1A Q16627 HCC-1(9-74) CCL14 Q16651 Prostasin lightchain PRSS8 Q16661 Guanylate cyclase C-activating peptide 2 GUCA2BQ16663 CCL15(29-92) CCL15 Q16674 Melanoma-derived growth regulatoryprotein MIA Q16769 Glutaminyl-peptide cyclotransferase QPCT Q16787Laminin subunit alpha-3 LAMA3 Q16842CMP-N-acetylneuraminate-beta-galactosamide- ST3GAL2alpha-2,3-sialyltransferase 2 Q17RR3 Pancreatic lipase-related protein 3PNLIPRP3 Q17RW2 Collagen alpha-1(XXIV) chain COL24A1 Q17RY6 Lymphocyteantigen 6K LY6K Q1L6U9 Prostate-associated microseminoprotein MSMPQ1W4C9 Serine protease inhibitor Kazal-type 13 SPINK13 Q1ZYL8 Izumosperm-egg fusion protein 4 IZUMO4 Q29960 HLA class I histocompatibilityantigen, Cw-16 HLA-C alpha chain Q2I0M5 R-spondin-4 RSPO4 Q2L4Q9 Serineprotease 53 PRSS53 Q2MKA7 R-spondin-1 RSPO1 Q2MV58 Tectonic-1 TCTN1Q2TAL6 Brorin VWC2 Q2UY09 Collagen alpha-1(XXVIII) chain COL28A1 Q2VPA4Complement component receptor 1-like protein CR1L Q2WEN9Carcinoembryonic antigen-related cell adhesion CEACAM16 molecule 16Q30KP8 Beta-defensin 136 DEFB136 Q30KP9 Beta-defensin 135 DEFB135 Q30KQ1Beta-defensin 133 DEFB133 Q30KQ2 Beta-defensin 130 DEFB130 Q30KQ4Beta-defensin 116 DEFB116 Q30KQ5 Beta-defensin 115 DEFB115 Q30KQ6Beta-defensin 114 DEFB114 Q30KQ7 Beta-defensin 113 DEFB113 Q30KQ8Beta-defensin 112 DEFB112 Q30KQ9 Beta-defensin 110 DEFB110 Q30KR1Beta-defensin 109 DEFB109P1 Q32P28 Prolyl 3-hydroxylase 1 LEPRE1 Q3B7J2Glucose-fructose oxidoreductase domain- GFOD2 containing protein 2Q3SY79 Protein Wnt WNT3A Q3T906 N-acetylglucosamine-1-phosphotransferaseGNPTAB subunits alpha/beta Q495T6 Membrane metallo-endopeptidase-like 1MMEL1 Q49AH0 Cerebral dopamine neurotrophic factor CDNF Q4G0G5Secretoglobin family 2B member 2 SCGB2B2 Q4G0M1 Protein FAM132B FAM132BQ4LDE5 Sushi, von Willebrand factor type A, EGF and SVEP1 pentraxindomain-containing protein 1 Q4QY38 Beta-defensin 134 DEFB134 Q4VAJ4Protein Wnt WNT10B Q4W5P6 Protein TMEM155 TMEM155 Q4ZHG4 Fibronectintype III domain-containing protein 1 FNDC1 Q53H76 Phospholipase A1member A PLA1A Q53RD9 Fibulin-7 FBLN7 Q53S33 BolA-like protein 3 BOLA3Q5BLP8 Neuropeptide-like protein C4orf48 C4orf48 Q5DT21 Serine proteaseinhibitor Kazal-type 9 SPINK9 Q5EBL8 PDZ domain-containing protein 11PDZD11 Q5FYB0 Arylsulfatase J ARSJ Q5FYB1 Arylsulfatase I ARSI Q5GAN3Ribonuclease-like protein 13 RNASE13 Q5GAN4 Ribonuclease-like protein 12RNASE12 Q5GAN6 Ribonuclease-like protein 10 RNASE10 Q5GFL6 vonWillebrand factor A domain-containing VWA2 protein 2 Q5H8A3 Neuromedin-SNMS Q5H8C1 FRAS1-related extracellular matrix protein 1 FREM1 Q5IJ48Protein crumbs homolog 2 CRB2 Q5J5C9 Beta-defensin 121 DEFB121 Q5JS37NHL repeat-containing protein 3 NHLRC3 Q5JTB6 Placenta-specific protein9 PLAC9 Q5JU69 Torsin-2A TOR2A Q5JXM2 Methyltransferase-like protein 24METTL24 Q5JZY3 Ephrin type-A receptor 10 EPHA10 Q5K4E3 Polyserase-2PRSS36 Q5SRR4 Lymphocyte antigen 6 complex locus protein G5c LY6G5CQ5T1H1 Protein eyes shut homolog EYS Q5T4F7 Secreted frizzled-relatedprotein 5 SFRP5 Q5T4W7 Artemin ARTN Q5T7M4 Protein FAM132A FAM132AQ5TEH8 Protein Wnt WNT2B Q5TIE3 von Willebrand factor Adomain-containing VWA5B1 protein 5B1 Q5UCC4 ER membrane protein complexsubunit 10 EMC10 Q5VST6 Abhydrolase domain-containing protein FAM108B1FAM108B1 Q5VTL7 Fibronectin type III domain-containing protein 7 FNDC7Q5VUM1 UPF0369 protein C6orf57 C6orf57 Q5VV43 Dyslexia-associatedprotein KIAA0319 KIAA0319 Q5VWW1 Complement C1q-like protein 3 C1QL3Q5VXI9 Lipase member N LIPN Q5VXJ0 Lipase member K LIPK Q5VXM1 CUBdomain-containing protein 2 CDCP2 Q5VYX0 Renalase RNLS Q5VYY2 Lipasemember M LIPM Q5W186 Cystatin-9 CST9 Q5W5W9 Regulated endocrine-specificprotein 18 RESP18 Q5XG92 Carboxylesterase 4A CES4A Q63HQ2 PikachurinEGFLAM Q641Q3 Meteorin-like protein METRNL Q66K79 Carboxypeptidase Z CPZQ685J3 Mucin-17 MUC17 Q68BL7 Olfactomedin-like protein 2A OLFML2A Q68BL8Olfactomedin-like protein 2B OLFML2B Q68DV7 E3 ubiquitin-protein ligaseRNF43 RNF43 Q6B9Z1 Insulin growth factor-like family member 4 IGFL4Q6BAA4 Fc receptor-like B FCRLB Q6E0U4 Dermokine DMKN Q6EMK4 VasorinVASN Q6FHJ7 Secreted frizzled-related protein 4 SFRP4 Q6GPI1Chymotrypsin B2 chain B CTRB2 Q6GTS8 Probable Carboxypeptidase PM20D1PM20D1 Q6H9L7 Isthmin-2 ISM2 Q6IE36 Ovostatin homolog 2 OVOS2 Q6IE37Ovostatin homolog 1 OVOS1 Q6IE38 Serine protease inhibitor Kazal-type 14SPINK14 Q6ISS4 Leukocyte-associated immunoglobulin-like LAIR2 receptor 2Q6JVE5 Epididymal-specific lipocalin-12 LCN12 Q6JVE6 Epididymal-specificlipocalin-10 LCN10 Q6JVE9 Epididymal-specific lipocalin-8 LCN8 Q6KF10Growth/differentiation factor 6 GDF6 Q6MZW2 Follistatin-related protein4 FSTL4 Q6NSX1 Coiled-coil domain-containing protein 70 CCDC70 Q6NT32Carboxylesterase 5A CES5A Q6NT52 Choriogonadotropin subunit beta variant2 CGB2 Q6NUI6 Chondroactherin-like protein CHADL Q6NUJ1 Saposin A-likePSAPL1 Q6P093 Arylacetamide deacetylase-like 2 AADACL2 Q6P4A8Phospholipase B-like 1 PLBD1 Q6P5S2 UPF0762 protein C6orf58 C6orf58Q6P988 Protein notum homolog NOTUM Q6PCB0 von Willebrand factor Adomain-containing VWA1 protein 1 Q6PDA7 Sperm-associated antigen 11ASPAG11A Q6PEW0 Inactive serine protease 54 PRSS54 Q6PEZ8 Podocan-likeprotein 1 PODNL1 Q6PKH6 Dehydrogenase/reductase SDR family member 4-DHRS4L2 like 2 Q6Q788 Apolipoprotein A-V APOA5 Q6SPF0 Atherin SAMD1Q6UDR6 Kunitz-type protease inhibitor 4 SPINT4 Q6URK8 Testis, prostateand placenta-expressed protein TEPP Q6UW01 Cerebellin-3 CBLN3 Q6UW10Surfactant-associated protein 2 SFTA2 Q6UW15 Regenerating islet-derivedprotein 3-gamma REG3G Q6UW32 Insulin growth factor-like family member 1IGFL1 Q6UW78 UPF0723 protein C11orf83 C11orf83 Q6UW88 Epigen EPGN Q6UWE3Colipase-like protein 2 CLPSL2 Q6UWF7 NXPE family member 4 NXPE4 Q6UWF9Protein FAM180A FAM180A Q6UWM5 GLIPR1-like protein 1 GLIPR1L1 Q6UWN8Serine protease inhibitor Kazal-type 6 SPINK6 Q6UWP2Dehydrogenase/reductase SDR family member 11 DHRS11 Q6UWP8 SuprabasinSBSN Q6UWQ5 Lysozyme-like protein 1 LYZL1 Q6UWQ7 Insulin growthfactor-like family member 2 IGFL2 Q6UWR7 Ectonucleotide ENPP6pyrophosphatase/phosphodiesterase family member 6 soluble form Q6UWT2Adropin ENHO Q6UWU2 Beta-galactosidase-1-like protein GLB1L Q6UWW0Lipocalin-15 LCN15 Q6UWX4 HHIP-like protein 2 HHIPL2 Q6UWY0Arylsulfatase K ARSK Q6UWY2 Serine protease 57 PRSS57 Q6UWY5Olfactomedin-like protein 1 OLFML1 Q6UX06 Olfactomedin-4 OLFM4 Q6UX07Dehydrogenase/reductase SDR family member 13 DHRS13 Q6UX39 Amelotin AMTNQ6UX46 Protein FAM150B FAM150B Q6UX73 UPF0764 protein C16orf89 C16orf89Q6UXB0 Protein FAM131A FAM131A Q6UXB1 Insulin growth factor-like familymember 3 IGFL3 Q6UXB2 VEGF co-regulated chemokine 1 CXCL17 Q6UXF7 C-typelectin domain family 18 member B CLEC18B Q6UXH0 Hepatocellularcarcinoma-associated protein TD26 C19orf80 Q6UXH1 Cysteine-rich withEGF-like domain protein 2 CRELD2 Q6UXH8 Collagen and calcium-binding EGFdomain- CCBE1 containing protein 1 Q6UXH9 Inactive serine protease PAMR1PAMR1 Q6UXI7 Vitrin VIT Q6UXI9 Nephronectin NPNT Q6UXN2 Trem-liketranscript 4 protein TREML4 Q6UXS0 C-type lectin domain family 19 memberA CLEC19A Q6UXT8 Protein FAM150A FAM150A Q6UXT9 Abhydrolasedomain-containing protein 15 ABHD15 Q6UXV4 Apolipoprotein O-like APOOLQ6UXX5 Inter-alpha-trypsin inhibitor heavy chain H6 ITIH6 Q6UXX9R-spondin-2 RSPO2 Q6UY14 ADAMTS-like protein 4 ADAMTSL4 Q6UY27 Prostateand testis expressed protein 2 PATE2 Q6W4X9 Mucin-6 MUC6 Q6WN34Chordin-like protein 2 CHRDL2 Q6WRI0 Immunoglobulin superfamily member10 IGSF10 Q6X4U4 Sclerostin domain-containing protein 1 SOSTDC1 Q6X784Zona pellucida-binding protein 2 ZPBP2 Q6XE38 Secretoglobin family 1Dmember 4 SCGB1D4 Q6XPR3 Repetin RPTN Q6XZB0 Lipase member I LIPI Q6ZMM2ADAMTS-like protein 5 ADAMTSL5 Q6ZMP0 Thrombospondin type-1domain-containing THSD4 protein 4 Q6ZNF0 Iron/zinc purple acidphosphatase-like protein PAPL Q6ZRI0 Otogelin OTOG Q6ZRP7 Sulfhydryloxidase 2 QSOX2 Q6ZWJ8 Kielin/chordin-like protein KCP Q75N90Fibrillin-3 FBN3 Q765I0 Urotensin-2B UTS2D Q76B58 Protein FAM5C FAM5CQ76LX8 A disintegrin and metalloproteinase with ADAMTS13 thrombospondinmotifs 13 Q76M96 Coiled-coil domain-containing protein 80 CCDC80 Q7L1S5Carbohydrate sulfotransferase 9 CHST9 Q7L513 Fc receptor-like A FCRLAQ7L8A9 Vasohibin-1 VASH1 Q7RTM1 Otopetrin-1 OTOP1 Q7RTW8 Otoancorin OTOAQ7RTY5 Serine protease 48 PRSS48 Q7RTY7 Ovochymase-1 OVCH1 Q7RTZ1Ovochymase-2 OVCH2 Q7Z304 MAM domain-containing protein 2 MAMDC2 Q7Z3S9Notch homolog 2 N-terminal-like protein NOTCH2NL Q7Z4H4 Intermedin-shortADM2 Q7Z4P5 Growth/differentiation factor 7 GDF7 Q7Z4R8 UPF0669 proteinC6orf120 C6orf120 Q7Z4W2 Lysozyme-like protein 2 LYZL2 Q7Z5A4 Serineprotease 42 PRSS42 Q7Z5A7 Protein FAM19A5 FAM19A5 Q7Z5A8 Protein FAM19A3FAM19A3 Q7Z5A9 Protein FAM19A1 FAM19A1 Q7Z5J1 Hydroxysteroid1-beta-dehydrogenase 1-like HSD11B1L protein Q7Z5L0 Vitelline membraneouter layer protein 1 homolog VMO1 Q7Z5L3 Complement C1q-like protein 2C1QL2 Q7Z5L7 Podocan PODN Q7Z5P4 17-beta-hydroxysteroid dehydrogenase 13HSD17B13 Q7Z5P9 Mucin-19 MUC19 Q7Z5Y6 Bone morphogenetic protein 8ABMP8A Q7Z7B7 Beta-defensin 132 DEFB132 Q7Z7B8 Beta-defensin 128 DEFB128Q7Z7C8 Transcription initiation factor TFIID subunit 8 TAF8 Q7Z7H5Transmembrane emp24 domain-containing protein 4 TMED4 Q86SG7 Lysozymeg-like protein 2 LYG2 Q86SI9 Protein CEI C5orf38 Q86TE4 Leucine zipperprotein 2 LUZP2 Q86TH1 ADAMTS-like protein 2 ADAMTSL2 Q86U17 Serpin A11SERPINA11 Q86UU9 Endokinin-A TAC4 Q86UW8 Hyaluronan and proteoglycanlink protein 4 HAPLN4 Q86UX2 Inter-alpha-trypsin inhibitor heavy chainH5 ITIH5 Q86V24 Adiponectin receptor protein 2 ADIPOR2 Q86VB7 Soluble CD163 CD163 Q86VR8 Four-jointed box protein 1 FJX1 Q86WD7 Serpin A9SERPINA9 Q86WN2 Interferon epsilon IFNE Q86WS3 Placenta-specific 1-likeprotein PLAC1L Q86X52 Chondroitin sulfate synthase 1 CHSY1 Q86XP6Gastrokine-2 GKN2 Q86XS5 Angiopoietin-related protein 5 ANGPTL5 Q86Y27 Bmelanoma antigen 5 BAGE5 Q86Y28 B melanoma antigen 4 BAGE4 Q86Y29 Bmelanoma antigen 3 BAGE3 Q86Y30 B melanoma antigen 2 BAGE2 Q86Y38Xylosyltransferase 1 XYLT1 Q86Y78 Ly6/PLAUR domain-containing protein 6LYPD6 Q86YD3 Transmembrane protein 25 TMEM25 Q86YJ6 Threoninesynthase-like 2 THNSL2 Q86YW7 Glycoprotein hormone beta-5 GPHB5 Q86Z23Complement C1q-like protein 4 C1QL4 Q8IU57 Interleukin-28 receptorsubunit alpha IL28RA Q8IUA0 WAP four-disulfide core domain protein 8WFDC8 Q8IUB2 WAP four-disulfide core domain protein 3 WFDC3 Q8IUB3Protein WFDC10B WFDC10B Q8IUB5 WAP four-disulfide core domain protein 13WFDC13 Q8IUH2 Protein CREG2 CREG2 Q8IUK5 Plexin domain-containingprotein 1 PLXDC1 Q8IUL8 Cartilage intermediate layer protein 2 C2 CILP2Q8IUX7 Adipocyte enhancer-binding protein 1 AEBP1 Q8IUX8 Epidermalgrowth factor-like protein 6 EGFL6 Q8IVL8 Carboxypeptidase O CPO Q8IVN8Somatomedin-B and thrombospondin type-1 SBSPON domain-containing proteinQ8IVW8 Protein spinster homolog 2 SPNS2 Q8IW75 Serpin A12 SERPINA12Q8IW92 Beta-galactosidase-1-like protein 2 GLB1L2 Q8IWL1 Pulmonarysurfactant-associated protein A2 SFTPA2 Q8IWL2 Pulmonarysurfactant-associated protein A1 SFTPA1 Q8IWV2 Contactin-4 CNTN4 Q8IWY4Signal peptide, CUB and EGF-like domain- SCUBE1 containing protein 1Q8IX30 Signal peptide, CUB and EGF-like domain- SCUBE3 containingprotein 3 Q8IXA5 Sperm acrosome membrane-associated protein 3, SPACA3membrane form Q8IXB1 DnaJ homolog subfamily C member 10 DNAJC10 Q8IXL6Extracellular serine/threonine protein kinase FAM20C Fam20C Q8IYD9 Lungadenoma susceptibility protein 2 LAS2 Q8IYP2 Serine protease 58 PRSS58Q8IYS5 Osteoclast-associated immunoglobulin-like OSCAR receptor Q8IZC6Collagen alpha-1(XXVII) chain COL27A1 Q8IZJ3 C3 and PZP-likealpha-2-macroglobulin domain- CPAMD8 containing protein 8 Q8IZN7Beta-defensin 107 DEFB107B Q8N0V4 Leucine-rich repeat LGI family member2 LGI2 Q8N104 Beta-defensin 106 DEFB106B Q8N119 Matrixmetalloproteinase-21 MMP21 Q8N129 Protein canopy homolog 4 CNPY4 Q8N135Leucine-rich repeat LGI family member 4 LGI4 Q8N145 Leucine-rich repeatLGI family member 3 LGI3 Q8N158 Glypican-2 GPC2 Q8N1E2 Lysozyme g-likeprotein 1 LYG1 Q8N2E2 von Willebrand factor D and EGF domain- VWDEcontaining protein Q8N2E6 Prosalusin TOR2A Q8N2S1 Latent-transforminggrowth factor beta-binding LTBP4 protein 4 Q8N302 Angiogenic factor withG patch and FHA domains 1 AGGF1 Q8N307 Mucin-20 MUC20 Q8N323 NXPE familymember 1 NXPE1 Q8N387 Mucin-15 MUC15 Q8N3Z0 Inactive serine protease 35PRSS35 Q8N436 Inactive carboxypeptidase-like protein X2 CPXM2 Q8N474Secreted frizzled-related protein 1 SFRP1 Q8N475 Follistatin-relatedprotein 5 FSTL5 Q8N4F0 BPI fold-containing family B member 2 BPIFB2Q8N4T0 Carboxypeptidase A6 CPA6 Q8N5W8 Protein FAM24B FAM24B Q8N687Beta-defensin 125 DEFB125 Q8N688 Beta-defensin 123 DEFB123 Q8N690Beta-defensin 119 DEFB119 Q8N6C5 Immunoglobulin superfamily member 1IGSF1 Q8N6C8 Leukocyte immunoglobulin-like receptor LILRA3 subfamily Amember 3 Q8N6G6 ADAMTS-like protein 1 ADAMTSL1 Q8N6Y2 Leucine-richrepeat-containing protein 17 LRRC17 Q8N729 Neuropeptide W-23 NPW Q8N8U9BMP-binding endothelial regulator protein BMPER Q8N907 DAN domain familymember 5 DAND5 Q8NAT1 Glycosyltransferase-like domain-containing GTDC2protein 2 Q8NAU1 Fibronectin type III domain-containing protein 5 FNDC5Q8NB37 Parkinson disease 7 domain-containing protein 1 PDDC1 Q8NBI3Draxin DRAXIN Q8NBM8 Prenylcysteine oxidase-like PCYOX1L Q8NBP7Proprotein convertase subtilisin/kexin type 9 PCSK9 Q8NBQ5 Estradiol17-beta-dehydrogenase 11 HSD17B11 Q8NBV8 Synaptotagmin-8 SYT8 Q8NCC3Group XV phospholipase A2 PLA2G15 Q8NCF0 C-type lectin domain family 18member C CLEC18C Q8NCW5 NAD(P)H-hydrate epimerase APOA1BP Q8NDA2Hemicentin-2 HMCN2 Q8NDX9 Lymphocyte antigen 6 complex locus protein G5bLY6G5B Q8NDZ4 Deleted in autism protein 1 C3orf58 Q8NEB7 Acrosin-bindingprotein ACRBP Q8NES8 Beta-defensin 124 DEFB124 Q8NET1 Beta-defensin 108BDEFB108B Q8NEX5 Protein WFDC9 WFDC9 Q8NEX6 Protein WFDC11 WFDC11 Q8NF86Serine protease 33 PRSS33 Q8NFM7 Interleukin-17 receptor D IL17RD Q8NFQ5BPI fold-containing family B member 6 BPIFB6 Q8NFQ6 BPI fold-containingfamily C protein BPIFC Q8NFU4 Follicular dendritic cell secreted peptideFDCSP Q8NFW1 Collagen alpha-1(XXII) chain COL22A1 Q8NG35 Beta-defensin105 DEFB105B Q8NG41 Neuropeptide B-23 NPB Q8NHW6 Otospiralin OTOS Q8NI99Angiopoietin-related protein 6 ANGPTL6 Q8TAA1 Probable ribonuclease 11RNASE11 Q8TAG5 V-set and transmembrane domain-containing VSTM2A protein2A Q8TAL6 Fin bud initiation factor homolog FIBIN Q8TAT2 Fibroblastgrowth factor-binding protein 3 FGFBP3 Q8TAX7 Mucin-7 MUC7 Q8TB22Spermatogenesis-associated protein 20 SPATA20 Q8TB73 Protein NDNF NDNFQ8TB96 T-cell immunomodulatory protein ITFG1 Q8TC92 Proteindisulfide-thiol oxidoreductase ENOX1 Q8TCV5 WAP four-disulfide coredomain protein 5 WFDC5 Q8TD06 Anterior gradient protein 3 homolog AGR3Q8TD33 Secretoglobin family 1C member 1 SCGB1C1 Q8TD46 Cell surfaceglycoprotein CD200 receptor 1 CD200R1 Q8TDE3 Ribonuclease 8 RNASE8Q8TDF5 Neuropilin and tolloid-like protein 1 NETO1 Q8TDL5 BPIfold-containing family B member 1 BPIFB1 Q8TE56 A disintegrin andmetalloproteinase with ADAMTS17 thrombospondin motifs 17 Q8TE57 Adisintegrin and metalloproteinase with ADAMTS16 thrombospondin motifs 16Q8TE58 A disintegrin and metalloproteinase with ADAMTS15 thrombospondinmotifs 15 Q8TE59 A disintegrin and metalloproteinase with ADAMTS19thrombospondin motifs 19 Q8TE60 A disintegrin and metalloproteinase withADAMTS18 thrombospondin motifs 18 Q8TE99 Acid phosphatase-like protein 2ACPL2 Q8TER0 Sushi, nidogen and EGF-like domain-containing SNED1 protein1 Q8TEU8 WAP, kazal, immunoglobulin, kunitz and NTR WFIKKN2domain-containing protein 2 Q8WTQ1 Beta-defensin 104 DEFB104B Q8WTR8Netrin-5 NTN5 Q8WTU2 Scavenger receptor cysteine-rich domain- SRCRB4Dcontaining group B protein Q8WU66 Protein TSPEAR TSPEAR Q8WUA8 TsukushinTSKU Q8WUF8 Protein FAM172A FAM172A Q8WUJ1 Neuferricin CYB5D2 Q8WUY1UPF0670 protein THEM6 THEM6 Q8WVN6 Secreted and transmembrane protein 1SECTM1 Q8WVQ1 Soluble calcium-activated nucleotidase 1 CANT1 Q8WWA0Intelectin-1 ITLN1 Q8WWG1 Neuregulin-4 NRG4 Q8WWQ2 Inactive heparanase-2HPSE2 Q8WWU7 Intelectin-2 ITLN2 Q8WWY7 WAP four-disulfide core domainprotein 12 WFDC12 Q8WWY8 Lipase member H LIPH Q8WWZ8 Oncoprotein-inducedtranscript 3 protein OIT3 Q8WX39 Epididymal-specific lipocalin-9 LCN9Q8WXA2 Prostate and testis expressed protein 1 PATE1 Q8WXD2Secretogranin-3 SCG3 Q8WXF3 Relaxin-3 A chain RLN3 Q8WXI7 Mucin-16 MUC16Q8WXQ8 Carboxypeptidase A5 CPA5 Q8WXS8 A disintegrin andmetalloproteinase with ADAMTS14 thrombospondin motifs 14 Q92484 Acidsphingomyelinase-like phosphodiesterase 3a SMPDL3A Q92485 Acidsphingomyelinase-like phosphodiesterase 3b SMPDL3B Q92496 Complementfactor H-related protein 4 CFHR4 Q92520 Protein FAM3C FAM3C Q92563Testican-2 SPOCK2 Q92583 C-C motif chemokine 17 CCL17 Q92626 Peroxidasinhomolog PXDN Q92743 Serine protease HTRA1 HTRA1 Q92752 Tenascin-R TNRQ92765 Secreted frizzled-related protein 3 FRZB Q92819 Hyaluronansynthase 2 HAS2 Q92820 Gamma-glutamyl hydrolase GGH Q92824 Proproteinconvertase subtilisin/kexin type 5 PCSK5 Q92832 Protein kinase C-bindingprotein NELL1 NELL1 Q92838 Ectodysplasin-A, membrane form EDA Q92874Deoxyribonuclease-1-like 2 DNASE1L2 Q92876 Kallikrein-6 KLK6 Q92913Fibroblast growth factor 13 FGF13 Q92954 Proteoglycan 4 C-terminal partPRG4 Q93038 Tumor necrosis factor receptor superfamily TNFRSF25 member25 Q93091 Ribonuclease K6 RNASE6 Q93097 Protein Wnt-2b WNT2B Q93098Protein Wnt-8b WNT8B Q95460 Major histocompatibility complex classI-related MR1 gene protein Q969D9 Thymic stromal lymphopoietin TSLPQ969E1 Liver-expressed antimicrobial peptide 2 LEAP2 Q969H8 UPF0556protein C19orf10 C19orf10 Q969Y0 NXPE family member 3 NXPE3 Q96A54Adiponectin receptor protein 1 ADIPOR1 Q96A83 Collagen alpha-1(XXVI)chain EMID2 Q96A84 EMI domain-containing protein 1 EMID1 Q96A98Tuberoinfundibular peptide of 39 residues PTH2 Q96A99 Pentraxin-4 PTX4Q96BH3 Epididymal sperm-binding protein 1 ELSPBP1 Q96BQ1 Protein FAM3DFAM3D Q96CG8 Collagen triple helix repeat-containing protein 1 CTHRC1Q96DA0 Zymogen granule protein 16 homolog B ZG16B Q96DN2 von Willebrandfactor C and EGF domain- VWCE containing protein Q96DR5 BPIfold-containing family A member 2 BPIFA2 Q96DR8 Mucin-like protein 1MUCL1 Q96DX4 RING finger and SPRY domain-containing protein 1 RSPRY1Q96EE4 Coiled-coil domain-containing protein 126 CCDC126 Q96GS6Abhydrolase domain-containing protein FAM108A1 FAM108A1 Q96GW7 Brevicancore protein BCAN Q96HF1 Secreted frizzled-related protein 2 SFRP2Q96I82 Kazal-type serine protease inhibitor domain- KAZALD1 containingprotein 1 Q96ID5 Immunoglobulin superfamily member 21 IGSF21 Q96II8Leucine-rich repeat and calponin homology LRCH3 domain-containingprotein 3 Q96IY4 Carboxypeptidase B2 CPB2 Q96JB6 Lysyl oxidase homolog 4LOXL4 Q96JK4 HHIP-like protein 1 HHIPL1 Q96KN2 Beta-Ala-His dipeptidaseCNDP1 Q96KW9 Protein SPACA7 SPACA7 Q96KX0 Lysozyme-like protein 4 LYZL4Q96L15 Ecto-ADP-ribosyltransferase 5 ART5 Q96LB8 Peptidoglycanrecognition protein 4 PGLYRP4 Q96LB9 Peptidoglycan recognition protein 3PGLYRP3 Q96LC7 Sialic acid-binding Ig-like lectin 10 SIGLEC10 Q96LR4Protein FAM19A4 FAM19A4 Q96MK3 Protein FAM20A FAM20A Q96MS3Glycosyltransferase 1 domain-containing protein 1 GLT1D1 Q96NY8Processed poliovirus receptor-related protein 4 PVRL4 Q96NZ8 WAP, kazal,immunoglobulin, kunitz and NTR WFIKKN1 domain-containing protein 1Q96NZ9 Proline-rich acidic protein 1 PRAP1 Q96P44 Collagen alpha-1(XXI)chain COL21A1 Q96PB7 Noelin-3 OLFM3 Q96PC5 Melanoma inhibitory activityprotein 2 MIA2 Q96PD5 N-acetylmuramoyl-L-alanine amidase PGLYRP2 Q96PH6Beta-defensin 118 DEFB118 Q96PL1 Secretoglobin family 3A member 2SCGB3A2 Q96PL2 Beta-tectorin TECTB Q96QH8 Sperm acrosome-associatedprotein 5 SPACA5 Q96QR1 Secretoglobin family 3A member 1 SCGB3A1 Q96QU1Protocadherin-15 PCDH15 Q96QV1 Hedgehog-interacting protein HHIP Q96RW7Hemicentin-1 HMCN1 Q96S42 Nodal homolog NODAL Q96S86 Hyaluronan andproteoglycan link protein 3 HAPLN3 Q96SL4 Glutathione peroxidase 7 GPX7Q96SM3 Probable carboxypeptidase X1 CPXM1 Q96T91 Glycoprotein hormonealpha-2 GPHA2 Q99062 Granulocyte colony-stimulating factor receptorCSF3R Q99102 Mucin-4 alpha chain MUC4 Q99217 Amelogenin, X isoform AMELXQ99218 Amelogenin, Y isoform AMELY Q99435 Protein kinase C-bindingprotein NELL2 NELL2 Q99470 Stromal cell-derived factor 2 SDF2 Q99542Matrix metalloproteinase-19 MMP19 Q99574 Neuroserpin SERPINI1 Q99584Protein S100-A13 S100A13 Q99616 C-C motif chemokine 13 CCL13 Q99645Epiphycan EPYC Q99674 Cell growth regulator with EF hand domain CGREF1protein 1 Q99715 Collagen alpha-1(XII) chain COL12A1 Q99727Metalloproteinase inhibitor 4 TIMP4 Q99731 C-C motif chemokine 19 CCL19Q99748 Neurturin NRTN Q99935 Proline-rich protein 1 PROL1 Q99942 E3ubiquitin-protein ligase RNF5 RNF5 Q99944 Epidermal growth factor-likeprotein 8 EGFL8 Q99954 Submaxillary gland androgen-regulated protein 3ASMR3A Q99969 Retinoic acid receptor responder protein 2 RARRES2 Q99972Myocilin MYOC Q99983 Osteomodulin OMD Q99985 Semaphorin-3C SEMA3C Q99988Growth/differentiation factor 15 GDF15 Q9BPW4 Apolipoprotein L4 APOL4Q9BQ08 Resistin-like beta RETNLB Q9BQ16 Testican-3 SPOCK3 Q9BQ51Programmed cell death 1 ligand 2 PDCD1LG2 Q9BQB4 Sclerostin SOST Q9BQI4Coiled-coil domain-containing protein 3 CCDC3 Q9BQP9 BPI fold-containingfamily A member 3 BPIFA3 Q9BQR3 Serine protease 27 PRSS27 Q9BQY6 WAPfour-disulfide core domain protein 6 WFDC6 Q9BRR6 ADP-dependentglucokinase ADPGK Q9BS86 Zona pellucida-binding protein 1 ZPBP Q9BSG0Protease-associated domain-containing protein 1 PRADC1 Q9BSG5 RetbindinRTBDN Q9BT30 Probable alpha-ketoglutarate-dependent ALKBH7 dioxygenaseABH7 Q9BT56 Spexin C12orG9 Q9BT67 NEDD4 family-interacting protein 1NDFIP1 Q9BTY2 Plasma alpha-L-fucosidase FUCA2 Q9BU40 Chordin-likeprotein 1 CHRDL1 Q9BUD6 Spondin-2 SPON2 Q9BUN1 Protein MENT MENT Q9BUR5Apolipoprotein O APOO Q9BV94 ER degradation-enhancingalpha-mannosidase-like 2 EDEM2 Q9BWP8 Collectin-11 COLEC11 Q9BWS9Chitinase domain-containing protein 1 CHID1 Q9BX67 Junctional adhesionmolecule C JAM3 Q9BX93 Group XIIB secretory phospholipase A2-likePLA2G12B protein Q9BXI9 Complement C1q tumor necrosis factor-relatedC1QTNF6 protein 6 Q9BXJ0 Complement C1q tumor necrosis factor-relatedC1QTNF5 protein 5 Q9BXJ1 Complement C1q tumor necrosis factor-relatedC1QTNF1 protein 1 Q9BXJ2 Complement C1q tumor necrosis factor-relatedC1QTNF7 protein 7 Q9BXJ3 Complement C1q tumor necrosis factor-relatedC1QTNF4 protein 4 Q9BXJ4 Complement C1q tumor necrosis factor-relatedC1QTNF3 protein 3 Q9BXJ5 Complement C1q tumor necrosis factor-relatedC1QTNF2 protein 2 Q9BXN1 Asporin ASPN Q9BXP8 Pappalysin-2 PAPPA2 Q9BXR6Complement factor H-related protein 5 CFHR5 Q9BXS0 Collagen alpha-1(XXV)chain COL25A1 Q9BXX0 EMILIN-2 EMILIN2 Q9BXY4 R-spondin-3 RSPO3 Q9BY15EGF-like module-containing mucin-like hormone EMR3 receptor-like 3subunit beta Q9BY50 Signal peptidase complex catalytic subunit SEC11CSEC11C Q9BY76 Angiopoietin-related protein 4 ANGPTL4 Q9BYF1 Processedangiotensin-converting enzyme 2 ACE2 Q9BYJ0 Fibroblast growthfactor-binding protein 2 FGFBP2 Q9BYW3 Beta-defensin 126 DEFB126 Q9BYX4Interferon-induced helicase C domain-containing IFIH1 protein 1 Q9BYZ8Regenerating islet-derived protein 4 REG4 Q9BZ76 Contactin-associatedprotein-like 3 CNTNAP3 Q9BZG9 Ly-6/neurotoxin-like protein 1 LYNX1Q9BZJ3 Tryptase delta TPSD1 Q9BZM1 Group XIIA secretory phospholipase A2PLA2G12A Q9BZM2 Group IIF secretory phospholipase A2 PLA2G2F Q9BZM5NKG2D ligand 2 ULBP2 Q9BZP6 Acidic mammalian chitinase CHIA Q9BZZ2Sialoadhesin SIGLEC1 Q9C0B6 Protein FAM5B FAM5B Q9GZM7Tubulointerstitial nephritis antigen-like TINAGL1 Q9GZN4 Brain-specificserine protease 4 PRSS22 Q9GZP0 Platelet-derived growth factor D,receptor-binding PDGFD form Q9GZT5 Protein Wnt-10a WNT10A Q9GZU5Nyctalopin NYX Q9GZV7 Hyaluronan and proteoglycan link protein 2 HAPLN2Q9GZV9 Fibroblast growth factor 23 FGF23 Q9GZX9 Twisted gastrulationprotein homolog 1 TWSG1 Q9GZZ7 GDNF family receptor alpha-4 GFRA4 Q9GZZ8Extracellular glycoprotein lacritin LACRT Q9H0B8 Cysteine-rich secretoryprotein LCCL domain- CRISPLD2 containing 2 Q9H106 Signal-regulatoryprotein delta SIRPD Q9H114 Cystatin-like 1 CSTL1 Q9H173 Nucleotideexchange factor SIL1 SIL1 Q9H1E1 Ribonuclease 7 RNASE7 Q9H1F0 WAPfour-disulfide core domain protein 10A WFDC10A Q9H1J5 Protein Wnt-8aWNT8A Q9H1J7 Protein Wnt-5b WNT5B Q9H1M3 Beta-defensin 129 DEFB129Q9H1M4 Beta-defensin 127 DEFB127 Q9H1Z8 Augurin C2orf40 Q9H239 Matrixmetalloproteinase-28 MMP28 Q9H2A7 C-X-C motif chemokine 16 CXCL16 Q9H2A9Carbohydrate sulfotransferase 8 CHST8 Q9H2R5 Kallikrein-15 KLK15 Q9H2X0Chordin CHRD Q9H2X3 C-type lectin domain family 4 member M CLEC4M Q9H306Matrix metalloproteinase-27 MMP27 Q9H324 A disintegrin andmetalloproteinase with ADAMTS10 thrombospondin motifs 10 Q9H336Cysteine-rich secretory protein LCCL domain- CRISPLD1 containing 1Q9H3E2 Sorting nexin-25 SNX25 Q9H3R2 Mucin-13 MUC13 Q9H3U7 SPARC-relatedmodular calcium-binding protein 2 SMOC2 Q9H3Y0 Peptidase inhibitorR3HDML R3HDML Q9H4A4 Aminopeptidase B RNPEP Q9H4F8 SPARC-related modularcalcium-binding protein 1 SMOC1 Q9H4G1 Cystatin-9-like CST9L Q9H5V8 CUBdomain-containing protein 1 CDCP1 Q9H6B9 Epoxide hydrolase 3 EPHX3Q9H6E4 Coiled-coil domain-containing protein 134 CCDC134 Q9H741 UPF0454protein C12orf49 C12orf49 Q9H772 Gremlin-2 GREM2 Q9H7Y0 Deleted inautism-related protein 1 CXorf36 Q9H8L6 Multimerin-2 MMRN2 Q9H9S5Fukutin-related protein FKRP Q9HAT2 Sialate O-acetylesterase SIAE Q9HB40Retinoid-inducible serine carboxypeptidase SCPEP1 Q9HB63 Netrin-4 NTN4Q9HBJ0 Placenta-specific protein 1 PLAC1 Q9HC23 Prokineticin-2 PROK2Q9HC57 WAP four-disulfide core domain protein 1 WFDC1 Q9HC73 Cytokinereceptor-like factor 2 CRLF2 Q9HC84 Mucin-5B MUC5B Q9HCB6 Spondin-1SPON1 Q9HCQ7 Neuropeptide NPSF NPVF Q9HCT0 Fibroblast growth factor 22FGF22 Q9HD89 Resistin RETN Q9NNX1 Tuftelin TUFT1 Q9NNX6 CD209 antigenCD209 Q9NP55 BPI fold-containing family A member 1 BPIFA1 Q9NP70Ameloblastin AMBN Q9NP95 Fibroblast growth factor 20 FGF20 Q9NP99Triggering receptor expressed on myeloid cells 1 TREM1 Q9NPA2 Matrixmetalloproteinase-25 MMP25 Q9NPE2 Neugrin NGRN Q9NPH0 Lysophosphatidicacid phosphatase type 6 ACP6 Q9NPH6 Odorant-binding protein 2b OBP2BQ9NQ30 Endothelial cell-specific molecule 1 ESM1 Q9NQ36 Signal peptide,CUB and EGF-like domain- SCUBE2 containing protein 2 Q9NQ38 Serineprotease inhibitor Kazal-type 5 SPINK5 Q9NQ76 Matrix extracellularphosphoglycoprotein MEPE Q9NQ79 Cartilage acidic protein 1 CRTAC1 Q9NR16Scavenger receptor cysteine-rich type 1 protein CD163L1 M160 Q9NR23Growth/differentiation factor 3 GDF3 Q9NR71 Neutral ceramidase ASAH2Q9NR99 Matrix-remodeling-associated protein 5 MXRA5 Q9NRA1Platelet-derived growth factor C PDGFC Q9NRC9 Otoraplin OTOR Q9NRE1Matrix metalloproteinase-26 MMP26 Q9NRJ3 C-C motif chemokine 28 CCL28Q9NRM1 Enamelin ENAM Q9NRN5 Olfactomedin-like protein 3 OLFML3 Q9NRR1Cytokine-like protein 1 CYTL1 Q9NS15 Latent-transforming growth factorbeta-binding LTBP3 protein 3 Q9NS62 Thrombospondin type-1domain-containing THSD1 protein 1 Q9NS71 Gastrokine-1 GKN1 Q9NS98Semaphorin-3G SEMA3G Q9NSA1 Fibroblast growth factor 21 FGF21 Q9NT22EMILIN-3 EMILIN3 Q9NTU7 Cerebellin-4 CBLN4 Q9NVR0 Kelch-like protein 11KLHL11 Q9NWH7 Spermatogenesis-associated protein 6 SPATA6 Q9NXC2Glucose-fructose oxidoreductase domain- GFOD1 containing protein 1Q9NY56 Odorant-binding protein 2a OBP2A Q9NY84 Vascular non-inflammatorymolecule 3 VNN3 Q9NZ20 Group 3 secretory phospholipase A2 PLA2G3 Q9NZC2Triggering receptor expressed on myeloid cells 2 TREM2 Q9NZK5 Adenosinedeaminase CECR1 CECR1 Q9NZK7 Group IIE secretory phospholipase A2PLA2G2E Q9NZP8 Complement C1r subcomponent-like protein C1RL Q9NZV1Cysteine-rich motor neuron 1 protein CRIM1 Q9NZW4 Dentin sialoproteinDSPP Q9P0G3 Kallikrein-14 KLK14 Q9P0W0 Interferon kappa IFNK Q9P218Collagen alpha-1(XX) chain COL20A1 Q9P2C4 Transmembrane protein 181TMEM181 Q9P2K2 Thioredoxin domain-containing protein 16 TXNDC16 Q9P2N4 Adisintegrin and metalloproteinase with ADAMTS9 thrombospondin motifs 9Q9UBC7 Galanin-like peptide GALP Q9UBD3 Cytokine SCM-1 beta XCL2 Q9UBD9Cardiotrophin-like cytokine factor 1 CLCF1 Q9UBM4 Opticin OPTC Q9UBP4Dickkopf-related protein 3 DKK3 Q9UBQ6 Exostosin-like 2 EXTL2 Q9UBR5Chemokine-like factor CKLF Q9UBS5 Gamma-aminobutyric acid type Breceptor subunit GABBR1 1 Q9UBT3 Dickkopf-related protein 4 short formDKK4 Q9UBU2 Dickkopf-related protein 2 DKK2 Q9UBU3 Ghrelin-28 GHRLQ9UBV4 Protein Wnt-16 WNT16 Q9UBX5 Fibulin-5 FBLN5 Q9UBX7 Kallikrein-11KLK11 Q9UEF7 Klotho KL Q9UFP1 Protein FAM198A FAM198A Q9UGM3 Deleted inmalignant brain tumors 1 protein DMBT1 Q9UGM5 Fetuin-B FETUB Q9UGP8Translocation protein SEC63 homolog SEC63 Q9UHF0 Neurokinin-B TAC3Q9UHF1 Epidermal growth factor-like protein 7 EGFL7 Q9UHG2 ProSAASPCSK1N Q9UHI8 A disintegrin and metalloproteinase with ADAMTS1thrombospondin motifs 1 Q9UHL4 Dipeptidyl peptidase 2 DPP7 Q9UI42Carboxypeptidase A4 CPA4 Q9UIG4 Psoriasis susceptibility 1 candidategene 2 protein PSORS1C2 Q9UIK5 Tomoregulin-2 TMEFF2 Q9UIQ6Leucyl-cystinyl aminopeptidase, pregnancy serum LNPEP form Q9UJA9Ectonucleotide ENPP5 pyrophosphatase/phosphodiesterase family member 5Q9UJH8 Meteorin METRN Q9UJJ9 N-acetylglucosamine-1-phosphotransferaseGNPTG subunit gamma Q9UJW2 Tubulointerstitial nephritis antigen TINAGQ9UK05 Growth/differentiation factor 2 GDF2 Q9UK55 Protein Z-dependentprotease inhibitor SERPINA10 Q9UK85 Dickkopf-like protein 1 DKKL1 Q9UKJ1Paired immunoglobulin-like type 2 receptor alpha PILRA Q9UKP4 Adisintegrin and metalloproteinase with ADAMTS7 thrombospondin motifs 7Q9UKP5 A disintegrin and metalloproteinase with ADAMTS6 thrombospondinmotifs 6 Q9UKQ2 Disintegrin and metalloproteinase domain- ADAM28containing protein 28 Q9UKQ9 Kallikrein-9 KLK9 Q9UKR0 Kallikrein-12KLK12 Q9UKR3 Kallikrein-13 KLK13 Q9UKU9 Angiopoietin-related protein 2ANGPTL2 Q9UKZ9 Procollagen C-endopeptidase enhancer 2 PCOLCE2 Q9UL52Transmembrane protease serine 11E non-catalytic TMPRSS11E chain Q9ULC0Endomucin EMCN Q9ULI3 Protein HEG homolog 1 HEG1 Q9ULZ1 Apelin-13 APLNQ9ULZ9 Matrix metalloproteinase-17 MMP17 Q9UM21Alpha-1,3-mannosyl-glycoprotein 4-beta-N- MGAT4Aacetylglucosaminyltransferase A soluble form Q9UM22 Mammalianependymin-related protein 1 EPDR1 Q9UM73 ALK tyrosine kinase receptorALK Q9UMD9 97 kDa linear IgA disease antigen COL17A1 Q9UMX5 NeudesinNENF Q9UN73 Protocadherin alpha-6 PCDHA6 Q9UNA0 A disintegrin andmetalloproteinase with ADAMTS5 thrombospondin motifs 5 Q9UNI1Chymotrypsin-like elastase family member 1 CELA1 Q9UNK4 Group IIDsecretory phospholipase A2 PLA2G2D Q9UP79 A disintegrin andmetalloproteinase with ADAMTS8 thrombospondin motifs 8 Q9UPZ6Thrombospondin type-1 domain-containing THSD7A protein 7A Q9UQ72Pregnancy-specific beta-1-glycoprotein 11 PSG11 Q9UQ74Pregnancy-specific beta-1-glycoprotein 8 PSG8 Q9UQC9 Calcium-activatedchloride channel regulator 2 CLCA2 Q9UQE7 Structural maintenance ofchromosomes protein 3 SMC3 Q9UQP3 Tenascin-N TNN Q9Y223UDP-N-acetylglucosamine 2-epimerase GNE Q9Y240 C-type lectin domainfamily 11 member A CLEC11A Q9Y251 Heparanase 8 kDa subunit HPSE Q9Y258C-C motif chemokine 26 CCL26 Q9Y264 Angiopoietin-4 ANGPT4 Q9Y275 Tumornecrosis factor ligand superfamily member TNFSF13B 13b, membrane formQ9Y287 BRI2 intracellular domain ITM2B Q9Y2E5 Epididymis-specificalpha-mannosidase MAN2B2 Q9Y334 von Willebrand factor Adomain-containing VWA7 protein 7 Q9Y337 Kallikrein-5 KLK5 Q9Y3B3Transmembrane emp24 domain-containing protein 7 TMED7 Q9Y3E2 BolA-likeprotein 1 BOLA1 Q9Y426 C2 domain-containing protein 2 C2CD2 Q9Y4K0 Lysyloxidase homolog 2 LOXL2 Q9Y4X3 C-C motif chemokine 27 CCL27 Q9Y5C1Angiopoietin-related protein 3 ANGPTL3 Q9Y5I2 Protocadherin alpha-10PCDHA10 Q9Y5I3 Protocadherin alpha-1 PCDHA1 Q9Y5K2 Kallikrein-4 KLK4Q9Y5L2 Hypoxia-inducible lipid droplet-associated protein HILPDA Q9Y5Q5Atrial natriuretic peptide-converting enzyme CORIN Q9Y5R2 Matrixmetalloproteinase-24 MMP24 Q9Y5U5 Tumor necrosis factor receptorsuperfamily TNFRSF18 member 18 Q9Y5W5 Wnt inhibitory factor 1 WIF1Q9Y5X9 Endothelial lipase LIPG Q9Y625 Secreted glypican-6 GPC6 Q9Y646Carboxypeptidase Q CPQ Q9Y6C2 EMILIN-1 EMILIN1 Q9Y6F9 Protein Wnt-6 WNT6Q9Y6I9 Testis-expressed sequence 264 protein TEX264 Q9Y6L7 Tolloid-likeprotein 2 TLL2 Q9Y6N3 Calcium-activated chloride channel regulatorCLCA3P family member 3 Q9Y6N6 Laminin subunit gamma-3 LAMC3 Q9Y6R7IgGFc-binding protein FCGBP Q9Y6Y9 Lymphocyte antigen 96 LY96 Q9Y6Z7Collectin-10 COLEC10

In some embodiments, the compositions and methods of the inventionprovide for the delivery of one or more mRNAs encoding one or moreadditional exemplary proteins listed in Table 2; thus, compositions ofthe invention may comprise an mRNA encoding a protein listed in Table 2(or a homolog thereof) along with other components set out herein, andmethods of the invention may comprise preparing and/or administering acomposition comprising an mRNA encoding a protein chosen from theproteins listed in Table 2 (or a homolog thereof) along with othercomponents set out herein.

In some embodiments, compositions and methods of the invention providefor the delivery of one or more nucleic acids that bind to or otherwiseact on an endogenous nucleic acid, such as endogenous mRNA or DNA, thatalter the transcription, translation, secretion, or action of one ormore proteins or genes listed in Table 2 (or a homolog thereof). Forexample, RNAi nucleic acids bind to endogenous mRNA, miRNA, or otherRNAs, while guide RNA (gRNA) and CRISPR RNA (crRNA) respectively bind toDNA and act on DNA in the nucleus. Accordingly, in embodiments, thecompositions and methods of the invention provide for delivery ofnucleic acids including one or more of RNAi nucleic acids, gRNA andcrRNA to interfere with the transcription, translation, secretion, oraction of one or more proteins or genes listed in Table 2 (and homologsthereof) along with other components set out herein.

TABLE 2 Additional Exemplary Proteins Uniprot ID Protein Name Gene NameA6NGW2 Putative stereocilin-like protein STRCP1 A6NIE9 Putative serineprotease 29 PRSS29P A6NJ16 Putative V-set and immunoglobulin IGHV4OR15-8domain-containing-like protein IGHV4OR15-8 A6NJS3 Putative V-set andimmunoglobulin IGHV1OR21-1 domain-containing-like protein IGHV1OR21-1A6NMY6 Putative annexin A2-like protein ANXA2P2 A8MT79 Putativezinc-alpha-2-glycoprotein-like 1 A8MWS1 Putative killer cellimmunoglobulin-like KIR3DP1 receptor like protein KIR3DP1 A8MXU0Putative beta-defensin 108A DEFB108P1 C9JUS6 Putativeadrenomedullin-5-like protein ADM5 P0C7V7 Putative signal peptidasecomplex SEC11B catalytic subunit SEC11B P0C854 Putative cat eye syndromecritical region CECR9 protein 9 Q13046 Putative pregnancy-specificbeta-1- PSG7 glycoprotein 7 Q16609 Putative apolipoprotein(a)-likeprotein 2 LPAL2 Q2TV78 Putative macrophage-stimulating protein MST1P9MSTP9 Q5JQD4 Putative peptide YY-3 PYY3 Q5R387 Putative inactive groupIIC secretory PLA2G2C phospholipase A2 Q5VSP4 Putative lipocalin 1-likeprotein 1 LCN1P1 Q5W188 Putative cystatin-9-like protein CST9LP1 CST9LP1Q6UXR4 Putative serpin A13 SERPINA13P Q86SH4 Putative testis-specificprion protein PRNT Q86YQ2 Putative latherin LATH Q8IVG9 Putative humaninpeptide MT-RNR2 Q8NHM4 Putative trypsin-6 TRY6 Q8NHW4 C-C motifchemokine 4-like CCL4L2 Q9H7L2 Putative killer cell immunoglobulin-likeKIR3DX1 receptor-like protein KIR3DX1 Q9NRI6 Putative peptide YY-2 PYY2Q9UF72 Putative TP73 antisense gene protein 1 TP73-AS1 Q9UKY3 Putativeinactive carboxylesterase 4 CES1P1

The Uniprot IDs set forth in Table 1 and Table 2 refer to the humanversions the listed proteins and the sequences of each are availablefrom the Uniprot database. Sequences of the listed proteins are alsogenerally available for various animals, including various mammals andanimals of veterinary or industrial interest. Accordingly, in someembodiments, compositions and methods of the invention provide for thedelivery of one or more mRNAs encoding one or more proteins chosen frommammalian homologs or homologs from an animal of veterinary orindustrial interest of the secreted proteins listed in Table 1 and Table2; thus, compositions of the invention may comprise an mRNA encoding aprotein chosen from mammalian homologs or homologs from an animal ofveterinary or industrial interest of a protein listed in Table 1 andTable 2 along with other components set out herein, and methods of theinvention may comprise preparing and/or administering a compositioncomprising an mRNA encoding a protein chosen from mammalian homologs orhomologs from an animal of veterinary or industrial interest of aprotein listed in Table 1 and Table 2 along with other components setout herein. In some embodiments, mammalian homologs are chosen frommouse, rat, hamster, gerbil, horse, pig, cow, llama, alpaca, mink, dog,cat, ferret, sheep, goat, or camel homologs. In some embodiments, theanimal of veterinary or industrial interest is chosen from the mammalslisted above and/or chicken, duck, turkey, salmon, catfish, or tilapia.

In embodiments, the compositions and methods of the invention providefor the delivery of mRNA encoding a protein chosen from Table 3. In someembodiments, the compositions and methods of the invention provide forthe delivery of one or more mRNAs encoding one or more proteins listedin Table 3; thus, compositions of the invention may comprise an mRNAencoding a protein listed in Table 3 (or a homolog thereof) along withother components set out herein, and methods of the invention maycomprise preparing and/or administering a composition comprising an mRNAencoding a protein chosen from the proteins listed in Table 3 (or ahomolog thereof) along with other components set out herein.

In some embodiments, compositions and methods of the invention providefor the delivery of one or more nucleic acids that bind to or otherwiseact on an endogenous nucleic acid, such as endogenous mRNA or DNA, thatalter the transcription, translation, secretion, or action of one ormore proteins listed in Table 3 (or a homolog thereof). For example,RNAi nucleic acids bind to endogenous mRNA, miRNA, or other RNAs, whileguide RNA (gRNA) and CRISPR RNA (crRNA) respectively bind to DNA and acton DNA in the nucleus. Accordingly, in embodiments, the compositions andmethods of the invention provide for delivery of nucleic acids includingone or more of RNAi nucleic acids, gRNA and crRNA to interfere with thetranscription, translation, secretion, or action of one or more proteinslisted in Table 3 (and homologs thereof) along with other components setout herein.

TABLE 3 Lysosomal and Related Proteins α-fucosidase α-galactosidaseα-glucosidase α-Iduronidase α-mannosidase α-N-acetylgalactosaminidase(α-galactosidase B) β-galactosidase β-glucuronidase β-hexosaminidaseβ-mannosidase 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase3-methylcrotonyl-CoA carboxylase 3-O-sulfogalactosyl cerebrosidesulfatase (arylsulfatase A) acetyl-CoA transferase acidalpha-glucosidase acid ceramidase acid lipase acid phosphatase acidsphingomyelinase alpha-galactosidase A arylsulfatase Abeta-galactosidase beta-glucocerebrosidase beta-hexosaminidasebiotinidase cathepsin A cathepsin K CLN3 CLN5 CLN6 CLN8 CLN9 cystinetransporter (cystinosin) cytosolic protein beta3A subunit of the adaptorprotein-3 complex, AP3 formyl-Glycine generating enzyme (FGE)galactocerebrosidase galactose-1-phosphate uridyltransferase (GALT)galactose 6-sulfate sulfatase (also known asN-acetylgalactosamine-6-sulfatase) glucocerebrosidase glucuronatesulfatase glucuronidase glycoprotein cleaving enzymes glycosaminoglycancleaving enzymes glycosylasparaginase (aspartylglucosaminidase) GM2-APHeparan-alpha-glucosaminide N-acetyltransferase (HGSNAT, TMEM76) Heparansulfatase hexosaminidase A lysosomal proteases methylmalonyl-CoA mutasehyaluronidase Iduronate sulfatase LAMP-2 lysosomal α-mannosidaseLysosomal p40 (C2orf18) Major facilitator superfamily domain containing8 protein (MFSD8 or CLN7) N-acetylgalactosamine 4-sulfatase N-acetylglucosamine 6-sulfatase N-acetyl glucosaminidaseN-acetylglucosamine-1-phosphate transferase NPC1 NPC2 palmitoyl-proteinthioesterase palmitoyl-protein thioesterase (CLN1) Saposin A(Sphingolipid activator protein A) Saposin B (Sphingolipid activatorprotein B) Saposin C (Sphingolipid activator protein C) Saposin D(Sphingolipid activator protein D) sialic acid transporter (sialin)sialidase Sialin sulfatase Transmembrane protein 74 (TMEM74)tripeptidyl-peptidase tripeptidyl-peptidase I (CLN2)UDP-N-acetylglucosamine-phosphotransferase

Information regarding lysosomal proteins is available from Lubke et al.,“Proteomics of the Lysosome,” Biochim Biophys Acta. (2009) 1793:625-635. In some embodiments, the protein listed in Table 3 and encodedby mRNA in the compositions and methods of the invention is a humanprotein. Sequences of the listed proteins are also available for variousanimals, including various mammals and animals of veterinary orindustrial interest as described above.

In some embodiments, the compositions and methods of the inventionprovide for the delivery of mRNA encoding a therapeutic protein (e.g.,cytosolic, transmembrane or secreted) such as those listed in Table 4.In some embodiments, the compositions and methods of the inventionprovide for the delivery of an mRNA encoding a therapeutic proteinuseful in treating a disease or disorder (i.e., indication) listed inTable 4; thus, compositions of the invention may comprise an mRNAencoding a therapeutic protein listed or not listed in Table 4 (or ahomolog thereof, as discussed below) along with other components set outherein for treating a disease or disorder (i.e., indication) listed inTable 4, and methods of the invention may comprise preparing and/oradministering a composition comprising an mRNA encoding a such a protein(or a homolog thereof, as discussed below) along with other componentsset out herein for treatment of a disease or disorder listed in Table 4.

In some embodiments, the compositions and methods of the inventionprovide for the delivery of one or more nucleic acids that bind to orotherwise act on an endogenous nucleic acid, such as endogenous mRNA orDNA, that alter the transcription, translation, secretion, or action ofone or more proteins listed in Table 4 (or homologs thereof) or proteinsuseful in treating a disease or disorder (i.e., indication) listed inTable 4. For example, RNAi nucleic acids bind to endogenous mRNA, miRNA,or other RNAs, while guide RNA (gRNA) and CRISPR RNA (crRNA)respectively bind to DNA and act on DNA in the nucleus. Accordingly, insome embodiments, the compositions and methods of the invention providefor delivery of nucleic acids including one or more of RNAi nucleicacids, gRNA and crRNA to interfere with the transcription, translation,secretion, or action of one or more proteins listed in Table 4 (andhomologs thereof) or proteins useful in treating a disease or disorder(i.e., indication) listed in Table 4, along with other components setout herein.

TABLE 4 Exemplary Indications and Related Proteins IndicationTherapeutic Protein 3-Methylcrotonyl-CoA carboxylase deficiencyMethylcrotonoyl-CoA carboxylase 3-Methylglutaconic aciduriaMethylglutaconyl-CoA hydratase Actinic keratosis Acute intermittentporphyria Porphobilinogen deaminase Acute lymphocytic leukemia Acutemyeloid leukemia Addison's disease Adenosine deaminase deficiencyAdenosine deaminase Adrenoleukodystrophy ABCD1 AdrenomyeloneuropathyAIDS/HIV Alcohol use disorders Alkaptonuria Homogentisate1,2-dioxygenase Allergic asthma Anti-IgE mAb Allergies (dermatitis,rhinitis) Alopecia areata Alpers' disease POLG Alpers-Huttenlochersyndrome Alpha 1-antitrypsin deficiency Alpha 1 protease inhibitorAlpha-mannosidosis Alpha-D-mannosidase Alport syndrome Alzheimer'sdisease Amyloid light-chain amyloidosis Amyotrophic lateral sclerosis(ALS) Anemia Erythropoietin Aortic valve stenosis Argininemia ArginaseArgininosuccinic acidemia Argininosuccinate lyase Arrhythmogenic rightventricular dysplasia Autism Autosomal dominant and recessiveprogressive external ophthalmoplegia with mitochondrial DNA deletionsAutosomal recessive polycystic kidney disease ARPKD Bacterial infectionsBasal cell carcinoma Batten disease Battenin + others B-cell chroniclymphocytic leukemia Becker muscular dystrophy DystrophinBeta-thalassemia Beta globin Binge eating disorder Bipolar disorderBladder cancer Blepharospasm, Cervical dystonia, Chronic migraine,Botulinum toxin more Bronchiolitis obliterans Brugada syndrome Buerger'sdisease CACNA1A CACNB4-related Episodic Ataxia Type 2 Cancer anddepression Cancer and sexual dysfunction Cancer in pregnancyCarbamylphosphate synthetase deficiency Carbamylphosphate synthetaseCarcinoma of the gallbladder Cardiomyopathy (diabetic) Cardiomyopathy(hypertrophic) Carnitine uptake defect SLC22A5 Catecholaminergicpolymorphic ventricular tachycardia CDKL5-related Atypical Rett SyndromeCeliac disease Cellulitis Cerebrovascular disease Cervix uteri cancerChronic fatigue syndrome Chronic graft versus host disease Chronicidiopathic urticaria Chronic immune thrombocytopenia ThrombopoietinChronic kidney kisease Chronic liver disease Chronic lymphocyticleukemia Chronic myeloid leukemia Chronic pancreatitis Cirrhosis of theliver Citrullinemia, type I Argininosuccinate synthase Classic RettSyndrome Classical galactosemia Galactose-1-phosphateuridylyltransferase Clostridium difficile associated diarrhea Clottingdisorders COAD/COPD Cocaine addiction COL4A5-related disorders Coldcontact urticaria Contraception, female Coronary artery diseases Corpusuteri cancer Corticobasal degeneration Crigler-Najjar syndromeUDP-glucuronosyltransferase Critical limb ischemia CTNS-relatedcystinosis Cutaneous lupus erythematosus Cutaneous neuroendocrinecarcinoma (Merkel Cell) Cystic fibrosis CFTR Cystic fibrosisDeoxyribonuclease I Cystinosis Cystinosin Cystinuria SLC7A9 Dementia(Lewy body) Depression Diabetic foot infections Diabetic foot ulcerDiabetic peripheral neuropathy Diabetic ulcers Diarrhoeal diseasesDiffuse large B-cell lymphoma DiGeorge syndrome Diverticulitis Drug usedisorders Duchenne muscular dystrophy Dystrophin Dysarthria Dyskinesia(levodopa-induced) Early-onset autosomal dominant Alzheimer's diseaseEczema Ehlers-Danlos syndrome, type 1 EIF2B1 EIF2B2 EIF2B3 EIF2B4EIF2B5-related childhood ataxia with central nervous systemhypomyelination/vanishing white matter Eosinophilic esophagitis EpilepsyErectile dysfunction Erythropoietic protoporphyria FerrochelataseEsophageal carcinoma Essential tremor Fabry disease Alpha galactosidaseFamilial adenomatous polyposis APC Familial chylomicronemia Lipoproteinlipase Familial dysbetalipoproteinemia Apolipoprotein E Familialisolated dilated cardiomyopathy Familial mediterranean fever Pyrin(MEFV) Familial melanoma Female infertility Follicle stimulating hormoneFemale sexual dysfunction Fibromyalgia FMR1-related disorders Fracturehealing Fragile X Premature Ovarian Failure Syndrome Fragile X syndromeFMRP Fragile X-Associated Tremor/Ataxia Syndrome Friedreich's ataxiaFrontotemporal dementia Fryns syndrome Galactocerebrosidase deficienciesGALE deficiency Galactose epimerase GALK deficiency GalactokinaseGALT-related galactosemia Gastric cancer Gastroesophageal reflux diseaseGaucher disease Glucocerebrosidase Gilbert syndromeUDP-glucuronosyltransferase Glioblastoma multiforme GlomerulonephritisGlutaric acidemia, type I Glutaryl-CoA dehydrogenase GM2 gangliosidosisHEXA, HEXB Gout Urate oxidase Graft versus host disease Growth hormonedeficiency Growth hormone 1/Growth hormone 2 Head and neck cancer,Metastatic colorectal cancer Anti-EGFr mAb Hearing loss, adult onsetHeart failure Hemachromatosis HFE protein Hemifacial spasm Hemolyticuremic syndrome Anti-complement factor C5 mAb Hemophilia A Factor VIIIHemophilia A, Hemophilia B Factor VII Hemophilia B Factor IX HepatitisB, Hepatitis C Interferon alpha HER2+ breast cancer, gastric cancerAnti-HER2 mAb Hereditary angioedema C1 esterase inhibitor Hereditaryhemorrhagic telangiectasia Hereditary hemorrhagic telangiectasia (AT)Hereditary spherocytosis Hidradenitis suppurativa HomocystinuriaCystathionine beta-synthase Homozygous familial hypercholesterolemia LDLreceptor Hunter syndrome (MPS II) Iduronate-2-sulfatase Huntingtondisease Huntingtin Hurler syndrome (MPS I) Alpha-L iduronidaseHydrolethalus Hyperalgesia Hyperbilirubinemia HyperhidrosisHyperlipidemia Hypermethioninemia Methionine adenosyltransferaseHyperoxaluria, type I Serine-pyruvate aminotransferase HypertensionHyperuricemia Hyponatremia Hypoparathyroidism Parathyroid hormoneHypophosphatasia TNSALP Idiopathic pulmonary fibrosis IminoglycinuriaImmunoglobulin deficiency Immunoglobulin Infection (adenovirus)Infection (anthrax prophylaxis) Infection (BK virus) Infection(Clostridium difficile prophylaxis) Infection (Dengue fever prophylaxis)Infection (Epstein-Barr virus) Infection (Hepatitis-D) Infection (Lymedisease prophylaxis) Infection (Smallpox virus) Infectious diseasesvaccines Infectious antigen Inflammatory heart diseases InsomniaInterstitial cystitis Iron-deficiency anaemia Irritable bowel diseaseIschaemic heart disease Isovaleric aciduria Isovaleric acid CoAdehydrogenase deficiency Jansky-Bielschowsky disease Juvenile Battendisease Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) Juvenilerheumatoid arthritis TNF-alpha inhibitors Kennedy's disease (SBMA)Keratoconus Krabbe disease Galactocerebrosidase Leber's hereditary opticneuropathy NADH dehydrogenase Leiomyosarcoma Lennox-Gastaut syndromeLesch-Nyhan syndrome Hypoxanthine phosphoribosyltransferase 1 LeukaemiaLi-Fraumeni syndrome TP53 Lipoma Liposarcoma Liver cancer Long-chain3-OH acyl-CoA dehydrogenase deficiency Long-chain-3-hydroxyacyl-CoAdehydrogenase Lower respiratory infections Lysosomal acid lipasedeficiency Lysosomal acid lipase Macular degeneration Major depressivedisorder Malignant fibrous histiocytoma Mantle cell lymphoma Maple syrupurine disease 3-methyl-2-oxobutanoate dehydrogenase Marfan syndrome FBN1Maroteaux-Lamy syndrome (MPS VI) N-acetylgalactosamine 4-sulfataseMastocytosis McArdle disease Muscle glycogen phosphorylase MECP2-relateddisorders MECP2-related Severe Neonatal Encephalopathy Medium-chainacyl-CoA dehydrogenase deficiency Acyl-CoA dehydrogenase MelanomaAnti-CTLA4 mAb Metachromatic leukodystrophy Arylsulfatase A Metastaticcolorectal cancer, NSCLC, others Anti-VEGF mAb Methylmalonyl-CoA mutasedeficiency Methylmalonyl-CoA mutase Migraine Mitochondrial oxidativephosphorylation disorders Morquio syndrome, type A (MPS IVA) Galactose6-sulfate sulfatase Morquio syndrome, type B (MPS IVB)Beta-galactosidase Mouth and oropharynx cancers Multiple carboxylasedeficiency Biotin-methylcrotonoyl-CoA-carboxylase ligase Multiplemyeloma Multiple sclerosis Anti-VLA-4 mAb Multiple sclerosis Interferonbeta Multiple system atrophy Myasthenia gravis Myelofibrosis NarcolepsyNeonatal bronchopulmonary dysplasia Neonatal infections Nephritis andnephrosis Neurofibromatosis, type 1 NF-1 Neuronal ceroidlipofuscinoses-related diseases Neutropenia G-CSF Niemann Pick disease,type A/B SMPD1 Niemann Pick disease, type C NPC1 Niemann-Pick diseaseType C1 Nocturia Non-alcoholic fatty liver disease Non-Hodgkin lymphomaAnti-CD20 mAb Non-small cell lung cancer Notch-3 related cerebralautosomal dominant arteriopathy with subcortical infarcts andleukoencephalopathy (CADASIL) Obesity Ophthalmoparesis Opioid inducedconstipation Ornithine transcarbamylase deficiency Ornithinetranscarbamylase Osteoarthritis Osteopetrosis Osteoporosis Anti-RANKLmAb Ovarian cancer Paget disease of bone Sequestosome 1 Pain Pancreaticcarcinoma Panic disorder Parkinson disease Paroxysmal nocturnalhemoglobinuria Anti-complement factor C5 Mab Pediculosis capitis (headlice) Pelizaeus-Merzbacher disease Pemphigus vulgaris Peptic ulcerdisease Peripheral neuropathy Peyronie's disease PhenylketonuriaPhenylalanine hydroxylase Pneumococcal infection prophylaxisPOLG-related sensory ataxic neuropathy Polycystic kidney diseasePolycystic ovary syndrome Polycythaemia vera Polymerase G-relateddisorders Polymorphous light eruption Pompe disease Alpha glucosidasePorphyria cutanea tarda Uroporphyrinogen decarboxylase Post herpeticneuralgia Post-organ transplant Pouchitis PPM-X Syndrome Prader-Willisyndrome Preeclampsia Premature ejaculation Prematurity and low birthweight Primary ciliary dyskinesia Primary glomerular diseases Primaryhumoral immune deficiencies (e.g., CVID) Immunoglobulin ProctitisProgressive multifocal leukoencephalopathy Progressive supranuclearpalsy Propionic acidemia Propionyl-CoA carboxylase Prostate cancerPsoriasis Anti-IL-12 & IL-23 mAb Psoriatic arthritis TNF-alphainhibitors PTT-1 Pulmonary arterial hypertension Pulmonary arterialhypertension Raynaud's phenomenon Refractive errors Renal cell carcinomaRestless leg syndrome Retinitis pigmentosa Rheumatic heart diseaseRheumatoid arthritis Anti-interleukin-6 (IL-6) mAb Rheumatoid arthritisT-cell costimulation blocker Rheumatoid arthritis TNF-alpha inhibitorRomano-Ward syndrome Rosacea Sanfilippo syndrome, type A (MPS IIIA)Heparan N-sulfatase Sanfilippo syndrome, type B (MPS IIIB)N-acetyl-alpha-D-glucosaminidase Santavuori-Haltia disease SchizophreniaSchnitzler syndrome Scleroderma SCN1A SCN1B-related seizure disordersShort-chain acyl-CoA dehydrogenase deficiency Butyryl-CoA dehydrogenaseSickle cell disease Hemoglobin SLC3A1-related disorders Small cell lungcancer SMN-1-related spinal muscular atrophy (SMA) Spinal muscularatrophy Survival motor neuron protein Squamous cell carcinoma of headand neck Stickler syndrome Stomach cancer Stroke prophylaxis Synovialsarcoma Systemic lupus erythematosus Anti-BAFF Systemic sclerosisTetrahydrobiopterin-deficient hyperphenylalaninemia TetrahydrobiopterinThromboangiitis obliterans Thrombotic disorders Thyroid cancer TPP1deficiencies Trachea, bronchus, lung cancers Tricuspid atresia TSC1TSC2-related tuberous sclerosis Type 2 diabetes mellitus Glucagon-likepeptide 1 (GLP-1) agonist Type 2 diabetes mellitus Insulin Tyrosinemia,type I Fumarylacetoacetase Ulcerative colitis Uterine fibroids Varicoseveins Venous thromboembolism Very long-chain acyl-CoA dehydrogenasedeficiency Long-chain-acyl-CoA dehydrogenase von Gierke's diseaseGlucose-6-phosphatase Von Hippel-Lindau disease pVHL Wegenergranulomatosis Wilson disease Wilson disease protein X-Linked adrenalhypoplasia X-linked adrenoleukodystrophy X-linked agammaglobulinemiaBruton's tyrosine kinase

In some embodiments, the present invention is used to prevent, treatand/or cure a subject affected with a disease or disorder listed orassociated with the proteins listed in Tables 1, 2, 3, or 4. In someembodiments, an mRNA encodes one or more of Cystic FibrosisTransmembrane Conductance Regulator (CFTR), argininosuccinate synthetase(ASS1), Factor IX, survival motor neuron 1 (SMN1), or phenylalaninehydroxylase (PAH). In some embodiments, one or more of a RNAi nucleicacid, gRNA and crRNA bind to endogenous nucleic acid, such as RNA orDNA, to modulate one or more of Cystic Fibrosis TransmembraneConductance Regulator (CFTR) protein, argininosuccinate synthetase(ASS1) protein, Factor IX, survival motor neuron 1 (SMN1) protein,phenylalanine hydroxylase (PAH) or a protein or gene that modulates suchproteins.

EXAMPLES Example 1. Synthesis of Thioacetate Starting Material (Scheme8)

In a typical procedure, 25 g of potassium thioacetate is dissolved in200 mL of ACS grade acetone and cooled in an ice bath. To this, 27.4 gof 2-bromoethanol is added to the cooled solution (the container is thenrinsed with 50 mL of acetone to ensure maximum transfer). The reactionis stirred for 24 hours, allowing the bath to come to room temperature.The solution is then filtered by gravity before removing the solvent byrotovap to give crude yellow oil. The resulting oil is dissolved in 500mL of DCM, washed twice with 200 mL of water and dried over sodiumsulfate before decanting and evaporating to give crude product (75-85%yield). The product is then purified by column chromatography(EtOAc:Heptane). ¹H NMR: 2.37 ppm (s, 3H); 2.64 ppm (broad —OH, 1H);3.08 ppm (t, 2H); 3.75 ppm (t, 2H).

Example 2. Production of Cyclophospholane Precursor

Phosphoryl trichloride and TEA were dissolved in 30 mL of DCM and cooledto −35° C. (IPA/CO₂ bath). The diol was added slowly keeping the tempbelow −20° C. and the product was brought to room temperature and mixedfor at least 1 hour. The solution was cooled again in IPA/CO₂. ATEA/thioester mixture in 3 volumes of DCM was added to the reactionslowly, keeping the temperature below −20° C. The solution was thenallowed to come to room temperature while mixing overnight The solutionwas filtered the filtrate was then concentrated by rotovap. Theresulting oil was dissolved in DCM and rinsed with bicarbonate/water.The organic layer was dried by MgSO₄, filtered and concentrated to givequantitative crude yield. ¹H NMR consistent with expected structure.

Example 3. Production of Poly(Phosphoester) Using Ring-OpeningPolymerization (ROP)

In a 50 mL round bottom flask, 2 g of monomer were charged into 20 mL ofanhydrous toluene and 7.6 mg of benzyl alcohol. The mixture was stirredfor 15 minutes under nitrogen and 13.4 mg of DBU was added via syringeand allowed to stir for 24 hours. After this time, the reaction wasquenched with excess acetic acid. The resulting polymer was precipitatedwith 20 volumes of diethyl ether to give 20% yield of polymer with Mw of900 Da.

Example 4. Production of Poly(Phosphoester) Using Ring-OpeningPolymerization (ROP) as a One-Pot Reaction Using Pendant Amine

A 100 mL round bottom flask was charged with 25 mL of DCM and sealedunder positive nitrogen pressure before adding 2 g of POCl₃. Thereaction mixture was cooled in IPA/CO₂ bath for 30 minutes before addingpremixed thioester/DCM/TEA solution (1.6 g/5 mL/1.4 g, respectively)slowly, never letting the solution rise above −20° C. After addition,stirring was continued and the reaction mixture was brought to roomtemperature for at least 1 hour. The solution was cooled in IPA/CO₂ bathfor at least 30 minutes and a premix of diol/DCM/TEA solution (1.57 g/3mL/2.6 g respectively) was added slowly. The reaction stirred for up to72 hours at room temperature. Upon completion, the reaction was filteredand the filtered solution was then added to 10 volumes of MTBE slowlywith constant stirring. The solids were removed by filtration and thefiltrate was concentrated under reduced pressure. The concentratedsolution was precipitated in 20 volumes of cold THF and decanted. Theproduct was re-dissolved in MeOH (5 volumes) and precipitated into THFagain. The product was filtered, and dried under vacuum to constant mass(0.5 g, 10% yield).

Example 5. Production of Poly(Phosphoester) Using Ring-OpeningPolymerization (ROP) as a One-Pot Reaction Using Amine within PolymerBackbone

A 100 mL round bottom flask was charged with 25 mL of DCM and sealedunder positive nitrogen pressure before adding 2 g POCl₃. The reactionmixture was cooled in IPA/CO₂ bath for 30 minutes before adding thepremixed thioester/DCM/TEA solution (1.6 g/5 mL/1.4 g, respectively)slowly, never letting the solution rise above −20° C. After addition,stirring was continued and the reaction mixture was brought to roomtemperature for at least 1 hour. After this time, the solution wascooled in IPA/CO₂ bath for at least 30 minutes and premixed diol/DCM/TEAsolution (1.57 g/3 mL/2.6 g respectively) was added slowly. The reactionstirred for up to 72 hours at room temperature and was then filtered.The filtered solution was then added to 10 volumes of MTBE slowly withconstant stirring and the resulting solids were removed by filtration.The filtrate was concentrated under reduced pressure. The resultingconcentrated solution precipitated in 20 volumes of cold THF. The THFwas decanted and the product was dissolved in MeOH (5 volumes) andprecipitated into THF again. After decantation, the solid was driedunder vacuum to constant mass (1.2 g 22% yield).

Example 6. Synthesis of Dinitrophenol Thioacetate Phosphate PrecursorStarting Material (One-Pot Example)

A 100 mL round bottom flask was charged with 75 mL of DCM and 3 g ofPOCl₃ and sealed under positive nitrogen pressure. The reaction mixturewas cooled in an ice bath for 30 minutes before slowly adding a premixedthioester/DCM/TEA solution (2.44 g/10 mL/1.8 g, respectively) slowly,never letting the solution rise above 20° C. After addition, stirringwas continued while the reaction mixture was brought to room temperaturefor at least 1 hour. After this time, the solution was cooled in icebath for at least 30 minutes. Upon cooling, a premixed phenol/DCM/TEAsolution (5.7 g/10 mL/4 g respectively) was slowly over the course of anhour and the reaction was stirred for up to 72 hours at ambienttemperature. Upon completion, the reaction was filtered and the filtratewas concentrated under reduced pressure. The resulting crude materialwas purified by silica gel chromatography with DCM/MeOH mixture (56%yield).

Example 7. Synthesis of Dinitrophenol Chlorophosphate Starting Material

In a glove bag, 16 g bisphenol phosphoryl chloride was charged to 100 mLround bottom flask. 25 mL of carbon tetrachloride was add to the flaskand the solution mixed to dissolve the solid. The sealed vessel wastransferred to a cooled in an ice bath for 30 minutes under N₂ andstirring was performed. 20 mL of a 3:7 HNO₃:H₂SO₄ solution was addedslowly through a drop funnel over 1 hour and allowed to stir overnight(16 hours). After this time, the reaction was washed with 200 mL of DCM,and the organic layer was separated and quenched with anhydrous sodiumcarbonate under N₂. The solution was then filtered and the solventevaporated to a constant mass. The product was used as-is in subsequentreactions (21 g crude, quantitative). ¹H NMR consistent with expectedstructure.

Example 8. Alternate Synthesis of Dinitrophenol Thioacetate Precursor

A 250 mL round bottom flask was charged with 10 g of dinitrophenolchlorophosphate with 100 mL of DCM under N₂. The reaction mixture wascooled in an IPA/CO₂ bath and mixed until a homogenous solution wasachieved. Slow addition of a premixed thioester/DCM/TEA solution (2.1g/10 mL/2.2 g) to the reaction vessel performed and mixed slowly overand hour. The reaction was brought to room temperature while stirringunder N₂ overnight. After this time, the reaction solution wasevaporated and the residue was dissolved in 100 mL of carbontetrachloride, filtered, and evaporated again to a constant mass (6.5 g,80% yield). NMR was consistent with desired product.

Example 9. Alternate Production of Poly(Phosphoester)

A 100 mL round bottom flask was charged with 25 mL of DCM and sealedunder positive nitrogen pressure before adding 2 g POCl₃. The reactionmixture was cooled in IPA/CO₂ bath for 30 minutes before adding premixedthioester/DCM/TEA solution (1.6 g/5 mL/1.4 g, respectively) slowly,never letting the solution rise above −20° C. After addition of themixture, stirring was continued and the reaction mixture was brought toroom temperature for at least 1 hour. The solution as cooled solution inIPA/CO₂ bath for at least 30 minutes. Upon cooling, a premixeddiol/DCM/TEA solution (1.57 g/3 mL/2.6 g respectively) was added and theresulting mixture was stirred for up to 72 hours at room temperature.After a given time, the reaction was filtered and the filtrate was addedto 10 volumes of MTBE slowly with constant stirring. The resultingsolids were removed by filtration and the filtrate was concentratedunder reduced pressure. The concentrated solution was precipitated in 20volumes of cold THF and the solvent was decanted. The product wasre-dissolved in MeOH (5 volumes) and precipitated into THF again. TheTHF was decanted and the product was dried under vacuum to constant mass(0.4 g, 32% yield).

Example 10. Alternate Production of Poly(Phosphoester)

TABLE A Reaction # Monomer Amine Conditions MW Notes 074

TEA DCM 12.8 kDa Dialyzed 079A

TEA DCM   24 kDa Dialyzed 079B

Polymer- bound scavenger (resin) DCM   24 kDa Dialyzed 086

Polymer- bound scavenger (resin) DCM   21 kDa Dilute in MeOH (filter),Remove and recrystallize in THF 087A

TEA DCM   45 kDa MTBE precipitation (filter), MeOH/THF recrystallization087B

TEA DCM   32 kDa Acidify reaction mixture, Toluene addition (oil out)MeOH/THF recrystallization 088

TEA DCM   69 kDa MeOH/Brine THF Precipitation 089

TEA DCM   24 kDa MeOH/Brine THF extracted 090

TEA DCM   7 kDa MeOH/EtOAc recrystallization

Example 11. Synthesis of Branched Poly(Phosphoester)

POCl₃ was dissolved in dichloromethane (5 mL) in a 100 mL round bottomflask. The solution was cooled with IPA/CO2 before adding thediol/TEA/DCM solution slowly. The reaction solution was stirred for 72hours, quenched with MeOH/ACN and the solvent was removed under reducedpressure to dryness yielding a crude yellow material. A portion of thematerial was dissolved and dialyzed against a 50/50 MeOH/phosphatebuffer solution for 24 hours resulting in a polymer with an approximatemolecular weight of 27 kDa.

Synthesis of Alternative Imidazole-Based Diol Monomers.

Exemplary imidazole-based diols are provided in Scheme 19.

Scheme 20 describes an exemplary synthesis of diol monomer 301.

Scheme 21 describes an exemplary synthesis of diol monomer 302.

Scheme 22 describes an exemplary synthesis of diol monomer 303.

Scheme 23 describes an exemplary synthesis of diol monomer 304.

Example 12. Synthesis of Diol Monomer 305

Scheme 24 describes an exemplary synthesis of diol monomer 305.

N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-(1-trityl-1H-imidazol-4-yl)propanamide(3)

To the mixture of 3-(1-trityl-1H-imidazol-4-yl)propanoic acid (1) (10.2g, 0.027 mol, 1.0 equiv) and HATU (10.2 g, 0.027 mol, 1.0 equiv) in DCM(200 mL) was added DIPEA (14 mL, 3.0 equiv), the resulting mixture wasstirred 5 min. at room temperature, and then(2,2-dimethyl-1,3-dioxolan-4-yl)methanamine (2) (3.5 g, 0.027 mol, 1.0equiv) was added. The mixture was stirred overnight at room temperature.The reaction mixture was washed with Brine (100 mL×3), and dried withanhydrous sodium sulfate. After the filtration, the organic solvent wasevaporated under vacuum and the residue was purified with an ISCO (330 gcolumn), eluted with 0-100% MeOH in DCM, collected 13 g (98%) of thedesired product 3.

(2,2-dimethyl-1,3-dioxolan-4-yl)methyl Methanesulfonate (5)

To the solution of (2,2-dimethyl-1,3-dioxolan-4-yl)methanol (4) (25 g,0.18 mol) in DCM (100 mL) was added TEA (30 mL, 0.32 mol) followed bythe addition of MsCl (16.3 mL, 0.15 mol) with ice bath cooling. Theresulting mixture was stirred for 2 h. at room temperature. The reactionmixture was then washed with cold water (100 mL×3), dried with anhydrousmagnesium sulfate. After filtration, the organic solvent was evaporatedunder vacuum and collected 37.2 g of crude product (5) that was used forthe next step without further purification.

4-(azidomethyl)-2,2-dimethyl-1,3-dioxolane (6)

To the solution of (2,2-dimethyl-1,3-dioxolan-4-yl)methylmethanesulfonate (7) (37.2 g, 0.18 mol) in DMF (100 mL) was added asolution of NaN₃ (16 g, 0.24 mol, 1.3 equiv) in water (100 mL). Theresulting mixture was heated overnight at 80-90° C. After the reactionwas cooled to room temperature, brine (400 mL) was added. Ether was usedto extract (200 mL×4), the combined ether was washed with brine (200mL×2) and water (200 mL×2), dried with anhydrous sodium sulfate. Afterthe filtration, the organic solvent was evaporated under vacuum andcollected 21.7 g of crude product (6) that was used for the next stepwithout further purification

(2,2-dimethyl-1,3-dioxolan-4-yl)methanamine (2)

To the solution 4-(azidomethyl)-2,2-dimethyl-1,3-dioxolane (6) (20 g) inMeOH (200 mL), Pd/C (10%, 5 g) was added, the resulting mixture waspurged with H₂ three times and stirred under H₂ balloon overnight. Thereaction mixture was passed through a Celite pad, washed with methanol.The filtrate was concentrated and purified with an ISCO (330 g column,eluted with 0-10% MeOH in DCM, collected 5.8 g (17%) desired product 2.

N-(2,3-dihydroxypropyl)-3-(1H-imidazol-4-yl)propanamide (Target 305)

To the solution ofN-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-(1-trityl-1H-imidazol-4-yl)propanamide(3) (13 g) in DCM (25 mL) and MeOH (25 mL) was added AcOH (100 mL). Theresulting reaction mixture was heated overnight at 70-80° C. Thereaction solution was cooled to room temperature and concentrated undervacuum. MeOH (50 mL) was added into the residue, the pH was adjusted to9-10 with 2M NaOH aqueous solution. After the filtration, the filtratewas purified with an ISCO, 330 g C-18 column, eluted with 0-100%MeOH/H₂O, collected 2.5 g (44%) of pure desired product (Target 305.)

Example 13. Synthesis of Diol Monomer 306

Scheme 25 describes an exemplary synthesis of diol monomer 306.

N-((2,2-dimethyl-1,3-dioxan-5-yl)methyl)-3-(1-trityl-1H-imidazol-4-yl)propanamide(3)

To the mixture of 3-(1-trityl-1H-imidazol-4-yl)propanoic acid (1) (15 g,0.039 mol, 1.0 equiv) and HATU (15 g, 0.039 mol, 1.0 equiv) in DCM (400mL), DIPEA (20 mL, 3.0 equiv) was added, the resulting mixture wasstirred 5 min. at room temperature, and(2,2-dimethyl-1,3-dioxan-5-yl)methanamine (4) (5.7 g, 0.039 mol, 1.0equiv) was added. The resulting mixture was stirred overnight at roomtemperature. The reaction mixture was washed with Brine (100 mL×3), anddried with anhydrous sodium sulfate. After the filtration, the organicsolvent was evaporated under vacuum and the residue was purified withISCO (330 column), eluted with 0-100% MeOH in DCM, collected 17.6 g(88%) desired product 3.

N-(3-hydroxy-2-(hydroxymethyl)propyl)-3-(1H-imidazol-4-yl)propanamide(Target 306)

To the solution ofN-((2,2-dimethyl-1,3-dioxan-5-yl)methyl)-3-(1-trityl-1H-imidazol-4-yl)propanamide(3) (17.6 g) in DCM (50 mL) and MeOH (50 mL) was added AcOH (100 mL).The resulting reaction mixture was heated overnight at 70-80° C. Thereaction solution was cooled to room temperature and concentrated undervacuum. MeOH (50 mL) was added into the residue, the pH was adjusted to9-10 with 2M NaOH aqueous solution. After the filtration, the filtratewas purified with ISCO, 330 g C-18 column, eluted with 0-100% MeOH/H₂O,collected 4.4 g (56%) pure desired product (Target 306.)

Example 14. Synthesis of Diol Monomer 307

Scheme 26 describes an exemplary synthesis of diol monomer 307.

(E)-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-(1-trityl-1H-imidazol-4-yl)acrylamide(3)

To the mixture of (E)-3-(1-trityl-1H-imidazol-4-yl)acrylic acid (1)(14.5 g, 0.038 mol, 1.0 equiv) and HATU (14.5 g, 0.038 mol, 1.0 equiv)in DCM (400 mL), DIPEA (19.6 mL, 3.0 equiv) was added, the resultingmixture was stirred 5 min. at room temperature, and(2,2-dimethyl-1,3-dioxan-5-yl)methanamine (4) (5.0 g, 0.038 mol, 1.0equiv) was added. The resulting mixture was stirred overnight at roomtemperature. The reaction mixture was washed with Brine (100 mL×3), anddried with anhydrous sodium sulfate. After filtration the organicsolvent was evaporated under vacuum and the residue was purified withISCO (330 g column), eluted with 0-100% MeOH in DCM, collected 17.1 g(90%) desired product 5.

(E)-N-(2,3-dihydroxypropyl)-3-(1H-imidazol-4-yl)acrylamide (Target 307)

To the solution of(E)-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-(1-trityl-1H-imidazol-4-yl)acrylamide(3) (17.1 g) in DCM (50 mL) and MeOH (50 mL) was added AcOH (100 mL).The resulting reaction mixture was heated overnight at 70-80° C. Thereaction solution was cooled to room temperature and concentrated undervacuum. MeOH (50 mL) was added into the residue, the pH was adjusted to9-10 with 2M NaOH aqueous solution. After filtration the filtrate waspurified with an ISCO, 330 g C-18 column, eluted with 0-100% MeOH/H₂O,collected 2.0 g (27%) pure desired product (Target 307.)

Example 15. Synthesis of Diol Monomer 308

Scheme 27 describes an exemplary synthesis of diol monomer 308.

Synthesis of (E)-3-(1-trityl-1H-imidazol-4-yl)acrylic Acid (3)

To the mixture of urocanic acid (1) (21.3 g, 0.154 mol, 1.0 equiv) andtrityl chloride (2) (43 g, 0.154 mol, 1.0 equiv) in anhydrous DMF (350mL) was added TEA (64.8 mL, 0.462 mol, 3.0 equiv). The mixture wasstirred overnight at room temperature. CHCl₃ (500 mL) was added and thesolution washed with Brine. The aqueous was further extracted with DCMand the combined organic phases were combined and dried over anhydroussodium sulfate. After filtration the organic solvent was evaporatedunder vacuum and the residue was purified with an ISCO (330 column),eluted with 0-15% MeOH in DCM, collected 28.4 g (48%) of the desiredproduct 3.

(E)-N-((2,2-dimethyl-1,3-dioxan-5-yl)methyl)-3-(1-trityl-1H-imidazol-4-yl)acrylamide(5)

To the mixture of (E)-3-(1-trityl-1H-imidazol-4-yl)acrylic acid (3) (15g, 0.039 mol, 1.0 equiv) and HATU (15 g, 0.039 mol, 1.0 equiv) in DCM(400 mL), was added DIPEA (20 mL, 3.0 equiv) and the resulting mixturewas stirred 5 min. at room temperature and then(2,2-dimethyl-1,3-dioxan-5-yl)methanamine (4) (5.7 g, 0.039 mol, 1.0equiv) was added. The mixture was stirred overnight at room temperature.The reaction mixture was then washed with Brine (100 mL×3), and driedwith anhydrous sodium sulfate. After the filtration, the organic solventwas evaporated under vacuum and the residue was purified with ISCO (330column), eluted with 0-100% MeOH in DCM, collected 18.2 g (91%) of thedesired product 5.

(2,2-dimethyl-1,3-dioxan-5-yl)methyl Methanesulfonate (7)

To the solution of (2,2-dimethyl-1,3-dioxan-5-yl)methanol (6) (20 g,0.137 mol, 1.0 equiv) in DCM (400 mL), was added TEA (45.4 mL, 0.32 mol,2.3 equiv), followed by the addition of MsCl (11.7 mL, 0.15 mol) withice bath cooling. The resulting mixture was stirred for 2 h. at roomtemperature. The reaction mixture was washed with cold water (100 mL×3),dried with anhydrous magnesium sulfate. After the filtration, theorganic solvent was evaporated under vacuum and collected 27 g of crudeproduct (7) that was used for the next step without furtherpurification.

5-(azidomethyl)-2,2-dimethyl-1,3-dioxane (8)

To the solution of (2,2-dimethyl-1,3-dioxan-5-yl)methyl methanesulfonate(7) (27 g, 0.12 mol) in DMF (100 mL) was added a solution of NaN₃ (11.7g, 0.18 mol, 1.5 equiv) in water (100 mL). The resulting mixture washeated overnight at 80-90° C. After the reaction was cooled to roomtemperature, brine (400 mL) was added. Ether was used to extract organicmaterial (200 mL×4) and the combined ether extracts were washed withbrine (200 mL×2) and water (200 mL×2) and dried with anhydrous sodiumsulfate. After filtration, the organic solvent was evaporated undervacuum and collected 15.7 g of crude product (8) that was used for thenext step without further purification.

(2,2-dimethyl-1,3-dioxan-5-yl)methanamine (4)

To the solution of 5-(azidomethyl)-2,2-dimethyl-1,3-dioxane (8) (15.7 g)in MeOH (200 mL) was added Pd/C (10%, 4.5 g) and the resulting mixturewas purged with H₂ gas three times and stirred under a H₂ balloonovernight. The reaction mixture was passed through a Celite pad, and thepad was washed with methanol. The filtrate was concentrated andcollected 11.5 g desired product 4 that was used for the next stepwithout further purification.

(E)-N-(3-hydroxy-2-(hydroxymethyl)propyl)-3-(1H-imidazol-4-yl)acrylamide(Target 308)

To the solution of(E)-N-((2,2-dimethyl-1,3-dioxan-5-yl)methyl)-3-(1-trityl-1H-imidazol-4-yl)acrylamide(5) (18.2 g) in DCM (50 mL) and MeOH (50 mL) was added AcOH (100 mL).The resulting reaction mixture was heated overnight at 70-80° C. Thereaction solution was cooled to room temperature and concentrated undervacuum. MeOH (50 mL) was added into the residue and the pH was adjustedto 9-10 with 2M NaOH aqueous solution. After filtration, the filtratewas purified with by ISCO, 330 g C-18 column, eluted with 0-100%MeOH/H₂O, collected 3.9 g (48%) pure desired product (Target 308.)

Examples of mRNA-Poly(phosphoester) Nanoparticles Example 16. Productionof Human Argininosuccinate Synthetase (hASS1) Poly(Phosphoester)Nanoparticles

A portion of poly(phosphoseter) 086 was dissolved in water and the pHwas adjusted to 6.5. The solution was treated with a 1 mL solution ofhASS1 mRNA (1 mg) and mixed resulting in a nanoparticle formation(N/P=10) with an average particle size of 89 nm.

Example 17. Production of hASS1 Poly(Phosphoester) Nanoparticles

A portion of poly(phosphoseter) 087A was dissolved in water and the pHwas adjusted to 6.5. The solution was treated with a 1 mL solution ofhASS1 mRNA (1 mg) and mixed resulting in a nanoparticle formation(N/P=10) with an average particle size of 92 nm. Example 21. Productionof hASS1 poly(phosphoester) nanoparticles

A portion of poly(phosphoseter) 087B was dissolved in water and the pHwas adjusted to 6.5. The solution was treated with a 1 mL solution ofhASS1 mRNA (1 mg) and mixed resulting in a nanoparticle formation(N/P=10) with an average particle size of 90 nm.

Codon-Optimized Sequence for Human Argininosuccinate Synthetase (ASS1)mRNA:

[SEQ ID NO.: 1] XAUGAGCAGCAAGGGCAGCGUGGUGCUGGCCUACAGCGGCGGCCUGGACACCAGCUGCAUCCUGGUGUGGCUGAAGGAGCAGGGCUACGACGUGAUCGCCUACCUGGCCAACAUCGGCCAGAAGGAGGACUUCGAGGAGGCCCGCAAGAAGGCCCUGAAGCUGGGCGCCAAGAAGGUGUUCAUCGAGGACGUGAGCCGCGAGUUCGUGGAGGAGUUCAUCUGGCCCGCCAUCCAGAGCAGCGCCCUGUACGAGGACCGCUACCUGCUGGGCACCAGCCUGGCCCGCCCCUGCAUCGCCCGCAAGCAGGUGGAGAUCGCCCAGCGCGAGGGCGCCAAGUACGUGAGCCACGGCGCCACCGGCAAGGGCAACGACCAGGUGCGCUUCGAGCUGAGCUGCUACAGCCUGGCCCCCCAGAUCAAGGUGAUCGCCCCCUGGCGCAUGCCCGAGUUCUACAACCGCUUCAAGGGCCGCAACGACCUGAUGGAGUACGCCAAGCAGCACGGCAUCCCCAUCCCCGUGACCCCCAAGAACCCCUGGAGCAUGGACGAGAACCUGAUGCACAUCAGCUACGAGGCCGGCAUCCUGGAGAACCCCAAGAACCAGGCCCCCCCCGGCCUGUACACCAAGACCCAGGACCCCGCCAAGGCCCCCAACACCCCCGACAUCCUGGAGAUCGAGUUCAAGAAGGGCGUGCCCGUGAAGGUGACCAACGUGAAGGACGGCACCACCCACCAGACCAGCCUGGAGCUGUUCAUGUACCUGAACGAGGUGGCCGGCAAGCACGGCGUGGGCCGCAUCGACAUCGUGGAGAACCGCUUCAUCGGCAUGAAGAGCCGCGGCAUCUACGAGACCCCCGCCGGCACCAUCCUGUACCACGCCCACCUGGACAUCGAGGCCUUCACCAUGGACCGCGAGGUGCGCAAGAUCAAGCAGGGCCUGGGCCUGAAGUUCGCCGAGCUGGUGUACACCGGCUUCUGGCACAGCCCCGAGUGCGAGUUCGUGCGCCACUGCAUCGCCAAGAGCCAGGAGCGCGUGGAGGGCAAGGUGCAGGUGAGCGUGCUGAAGGGCCAGGUGUACAUCCUGGGCCGCGAGAGCCCCCUGAGCCUGUACAACGAGGAGCUGGUGAGCAUGAACGUGCAGGGCGACUACGAGCCCACCGACGCCACCGGCUUCAUCAACAUCAACAGCCUGCGCCUGAAGGAGUACCACCGCCUGCAGAGCAA GGUGACCGCCAAGUGAY5′ and 3′ UTR Sequences X (5′ UTR Sequence) = [SEQ ID NO.: 2]GGACAGAUCGCCUGGAGACGCCAUCCACGCUGUUUUGACCUCCAUAGAAGACACCGGGACCGAUCCAGCCUCCGCGGCCGGGAACGGUGCAUUGGAACGCGGAUUCCCCGUGCCAAGAGUGACUCACCGUCCUUGACACG Y (3′ UTR Sequence) =[SEQ ID NO.: 3] CGGGUGGCAUCCCUGUGACCCCUCCCCAGUGCCUCUCCUGGCCCUGGAAGUUGCCACUCCAGUGCCCACCAGCCUUGUCCUAAUAAAAUUAAGUUGCAUCAA GCU OR(SEQ ID NO.: 4) GGGUGGCAUCCCUGUGACCCCUCCCCAGUGCCUCUCCUGGCCCUGGAAGUUGCCACUCCAGUGCCCACCAGCCUUGUCCUAAUAAAAUUAAGUUGCAUCAAA GCU

While a number of embodiments of this invention have been described, itis apparent that the basic examples may be altered to provide otherembodiments that utilize the compounds, methods, and processes of thisinvention. Therefore, it will be appreciated that the scope of thisinvention is to be defined by the appended claims rather than by thespecific embodiments that have been represented by way of exampleherein.

1. A polymer comprising the moiety A: A, which is a moiety of formulaI:

or a pharmaceutically acceptable salt thereof, wherein: each instance ofR¹ independently is —H or a C₁-C₂₀ aliphatic group; each instance of R²independently is —H or a C₁-C₂₀ aliphatic group; each instance of R³independently is —H or a C₁-C₂₀ aliphatic group; X is independently S orO; n1 is an integer from 1 to 6; n2 is an integer from 1 to 6; R is N orCH; and L is C₁₋₆ alkyl or a protonatable group provided that when R isCH then L is a protonatable group, wherein the protonatable groupcomprises at least one 1° amino, 2° amino, 3° amino or imidazolyl group.2. The polymer of claim 1, wherein R¹ independently is —H, —CH₃, or—CH₂CH₃.
 3. The polymer of claim 1, wherein R² independently is —H,—CH₃, or —CH₂CH₃.
 4. The polymer of claim 1, wherein R³ independently is—H, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, CH(CH₃)₂, or C(CH₃)₃.
 5. The polymer ofclaim 1, wherein X is independently O or S. 6.-7. (canceled)
 8. Thepolymer of claim 1, wherein the polymer is a homopolymer comprising thestructure:

wherein: m is an integer such that the weight average molecular weight(M_(w)) of the polymer is about 10 kDa to about 60 kDa.
 9. (canceled)10. The polymer of claim 1, wherein the polymer is a copolymercomprising: m₁ instances of A and m₂ instances of B, wherein: B is amoiety of formula I different from A; and m₁ and m₂ are integers suchthat the weight average molecular weight (M_(w)) of the polymer is about10 kDa to about 60 kDa.
 11. (canceled)
 12. The polymer of claim 10,wherein the polymer is an alternating copolymer comprising thestructure:

wherein: B is a moiety of formula I different from A; and m′ is aninteger such that the weight average molecular weight (M_(w)) of thepolymer is about 10 kDa to about 60 kDa.
 13. (canceled)
 14. The polymerof claim 10, wherein the polymer is a block copolymer comprising thestructure:

wherein: B is a moiety of formula I different from A; and m₁ and m₂ areintegers such that the weight average molecular weight (M_(w)) of thepolymer is about 10 kDa to about 60 kDa.
 15. The polymer of claim 1,wherein, in moiety A: R is N; and L is C₁₋₆ alkyl; R is CH; and L is aprotonatable group; or R is N; and L is a protonatable group. 16.-17.(canceled)
 18. The polymer of claim 1, wherein: L is a protonatablegroup such that at least one conjugate acid of L-H has a pKa in water ofabout 4.5 to about 11.5.
 19. The polymer of claim 1, comprising themoiety: AT wherein: T is a targeting group.
 20. A pharmaceuticalcomposition comprising: the polymer of claim 1; and one or morepolynucleotides.
 21. The pharmaceutical composition of claim 20, whereinthe one or more polynucleotides comprise RNA, wherein the RNA isselected from the group consisting of mRNA, siRNA, snoRNA, microRNA,gRNA, crRNA, and combinations thereof.
 22. (canceled)
 23. Thepharmaceutical composition of claim 21, wherein the RNA is mRNA.
 24. Thepharmaceutical composition of claim 23, wherein the mRNA encodes apeptide, a polypeptide, or an enzyme.
 25. (canceled)
 26. Thepharmaceutical composition of claim 23, wherein the mRNA encodes cysticfibrosis transmembrane conductance regulator (CFTR) protein for use inthe delivery to or treatment of the lung of a subject or a lung cell.27. (canceled)
 28. The pharmaceutical composition of claim 23, whereinthe mRNA encodes ornithine transcarbamylase (OTC) protein for use in thedelivery to or treatment of the liver of a subject or a liver cell. 29.(canceled)
 30. The pharmaceutical composition of claim 23, wherein themRNA encodes a peptide or polypeptide for use in vaccine, and whereinthe mRNA encodes an antigen.
 31. (canceled)
 32. A method of treating adisease in a subject, comprising administering to the subject aneffective amount of the pharmaceutical composition of claim 20.